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At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, persons ≥65 years of age and healthcare personnel represented the most vulnerable groups with respect to risk of infection, severe illness, and death. However, as the pandemic progressed, there was an increasingly detrimental effect on young children and adolescents. Severe disease and hospitalization increased over time in pediatric populations, and containment measures created substantial psychosocial, educational, and economic challenges for young people. Vaccination of children against COVID-19 has been shown to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and severe outcomes in pediatric populations and may also help to prevent the spread of variants of concern and improve community immunity. This review discusses the burden of COVID-19 on children throughout the pandemic, the role of children in disease transmission, and the impact of COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

Pathogenic Bacillus and clostridial (i.e., Clostridium and Clostridioides) bacteria express a diverse repertoire of effector proteins to promote disease. This includes production of binary toxins, which enter host epithelial cells and seriously damage the intestinal tracts of insects, animals, and humans. In particular, binary toxins form an AB-type complex composed of a catalytic subunit that is toxic (A) and an oligomeric cell-binding and delivery subunit (B), where upon delivery of A into the cytoplasm of the host cell it catalytically ADP-ribosylates actin and rapidly induces host cell death. In this review, binary toxins expressed by Bacillus thuringiensis, Clostridioides difficile, and Clostridium perfringens will be discussed, with particular focus placed upon the structural elucidations of their respective B subunits and how these findings help to deconvolute how toxic enzyme delivery into target host cells is achieved by these deadly bacteria. [ABSTRACT FROM AUTHOR]

N95 respirator contamination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during clinical care of patients with coronavirus disease 2019 is poorly understood. We performed a prospective observational study on healthcare provider's (HCP's) N95 respirators' and face shields' SARS-CoV-2 contamination during aerosol-generating procedures on SARS-CoV-2–positive patients housed in a COVID-19–specific unit. Medical masks worn on top of HCP's N95 respirators, and under face shields, during study aerosol-generating procedures were used as surrogates to detect contamination to avoid waste. Thirty-three HCPs were studied, and a total of 33 mask and 27 face shields were sampled. Masks were cut into 9 pieces and face shields were sampled twice, front and back, to determine locality of contamination; however, no positive samples were identified using standard polymerase chain reaction techniques with a CT value up to 40. All 9 mask piece samples were then pooled, as were face shield samples, using centrifugal concentration with polyethersulfone membranes. Once pooled and concentrated, overall, 9 (15%) samples were positive via real-time polymerase chain reaction: 5 from masks (15.2%) and 4 from face shields (14.8%). [ABSTRACT FROM AUTHOR]

Few studies have described changes in SARS-CoV-2 antibody levels in response to infection and vaccination at frequent intervals and over extended follow-up periods. The purpose of this study was to assess changes in SARS-CoV-2–specific antibody responses among a prospective cohort of health care personnel over 18 months with up to 22 samples per person. Antibody levels and live virus neutralization were measured before and after mRNA-based vaccination with results stratified by (1) SARS-CoV-2 infection status prior to initial vaccination and (2) SARS-CoV-2 infection at any point during follow-up. We found that the antibody response to the first dose was almost 2-fold higher in individuals who were seropositive prior to vaccination, although neutralization titers were more variable. The antibody response induced by vaccination appeared to wane over time but generally persisted for 8 to 9 months, and those who were infected at any point during the study had slightly higher antibody levels over time vs those who remained uninfected. These findings underscore the need to account for SARS-CoV-2 natural infection as a modifier of vaccine responses, and they highlight the importance of frequent testing of longitudinal antibody titers over time. Together, our results provide a clearer understanding of the trajectories of antibody response among vaccinated individuals with and without prior SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Immune mediated graft loss still represents a major risk to transplant recipients. Creative approaches to immunosuppression that exploit the recipient's own alloregulatory mechanisms could reduce the need for pharmacologic immunosuppression and potentially induce immune tolerance. In the process of studying recipient derived myeloid derived suppressor cells (MDSCs), we identified key alloregulatory MDSC mechanisms, mediated by isolatable proteins IL-4, IL-34, and IL-10. We sought to purify these proteins and fuse them for subsequent infusion into transplant recipients as a means of inducing an alloregulatory response. In this introductory investigation, we leveraged molecular engineering technology to create a fusion protein (FP) of three cytokine coding sequences of IL-4, IL-34, and IL-10 and demonstrated their expressions by Western Blot analysis. Following purification, we tested whether FP IL-4/IL-34/IL-10 (FP1) can protect heart transplant allografts. Injection of FP1 significantly prolonged allogeneic cardiac graft survival in a dose-dependent fashion and the increase of graft survival time exceeded survival attributable to IL-34 alone. In vitro, MDSCs cells were expanded by FP1 treatment. However, FP1 did not directly inhibit T cell proliferation in vitro. In conclusion, newly developed FP1 improves the graft survival in cardiac transplantation mouse model. Significant additional work to optimize FP1 or include other novel proteins could supplement current treatment options for transplant patients. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations. [ABSTRACT FROM AUTHOR]

Heterogeneous ribonuclear protein A18 (hnRNP A18) is an RNA binding protein (RBP) involved in the hypoxic cellular stress response and regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in melanoma, breast cancer, prostate cancer, and colon cancer solid tumors. hnRNP A18 is comprised of an N-terminal structured RNA recognition motif (RMM) and a C-terminal intrinsically disordered domain (IDD). Upon cellar stressors, such as UV and hypoxia, hnRNP A18 is phosphorylated by casein kinase 2 (CK2) and glycogen synthase kinase 3β (GSK-3β). After phosphorylation, hnRNP A18 translocates from the nucleus to the cytosol where it interacts with pro-survival mRNA transcripts for proteins such as hypoxia inducible factor 1α and CTLA-4. Both the hypoxic cellular response and modulation of immune checkpoints by cancer cells promote chemoradiation resistance and metastasis. In this study, the 1 H, 13 C, and 15 N backbone and sidechain resonances of the 172 amino acid hnRNP A18 were assigned sequence-specifically and provide a framework for future NMR-based drug discovery studies toward targeting hnRNP A18. These data will also enable the investigation of the dynamic structural changes within the IDD of hnRNP A18 upon phosphorylation by CK2 and GSK-3β to provide critical insight into the structure and function of IDDs. [ABSTRACT FROM AUTHOR]

The immune deficiency (IMD) pathway directs host defense in arthropods upon bacterial infection. In Pancrustacea, peptidoglycan recognition proteins sense microbial moieties and initiate nuclear factor-κB-driven immune responses. Proteins that elicit the IMD pathway in non-insect arthropods remain elusive. Here, we show that an Ixodes scapularis homolog of croquemort (Crq), a CD36-like protein, promotes activation of the tick IMD pathway. Crq exhibits plasma membrane localization and binds the lipid agonist 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol. Crq regulates the IMD and jun N-terminal kinase signaling cascades and limits the acquisition of the Lyme disease spirochete B. burgdorferi. Additionally, nymphs silenced for crq display impaired feeding and delayed molting to adulthood due to a deficiency in ecdysteroid synthesis. Collectively, we establish a distinct mechanism for arthropod immunity outside of insects and crustaceans [ABSTRACT FROM AUTHOR]

Environmental cleaning and disinfection practices have been shown to reduce microorganism bioburden in the healthcare environment. This study was performed in four intensive care units in Thailand. Five high-touch surfaces were sampled before and after terminal manual cleaning and disinfection, and after pulsed xenon UV (PX-UV). Five nursing station sites were collected on a weekly basis before and after terminal manual cleaning. There were 100 patient rooms—50 rooms in the intervention arm and 50 rooms in the control arm—plus 32 nursing station sites. In the intervention arm, rooms with positive Gram-negative microorganisms were reduced by 50% after terminal manual cleaning and disinfection (p = 0.04) and 100% after PX-UV disinfection (p < 0.001). On five nursing station sites, colony counts of Gram-negative contamination decreased by 100% (p < 0.001) in the intervention arm while decreasing by 65.2% (p = 0.03) in the control arm after terminal manual cleaning and disinfection. The in-room time use was 15.6 min per room. A PX-UV device significantly reduced the level of Gram-negative microorganisms on high-touch surfaces in intensive care units. The application of a PX-UV device was practical a in resource-limited setting without compromising cleaning and disinfection times. [ABSTRACT FROM AUTHOR]

Background The role of ivermectin in the treatment of moderate coronavirus disease 2019 (COVID-19) is controversial. We performed an open label randomized controlled trial to evaluate the role of ivermectin plus favipiravir-based standard of care versus favipiravir-based standard of care for the treatment of moderate COVID-19 infection. Materials and Methods An open-label randomized control trial was performed at Thammasat Field Hospital and Thammasat University Hospital from October 1st, 2021 to May 31st, 2022. Patients with moderate COVID-19 infections were randomized to the intervention (ivermectin plus favipiravir-based standard of care) or control group (favipiravir-based standard of care alone). Patients were followed up to 21 days. The primary outcome was the improvement in World Health Organization (WHO) category ordinal scale by 2 points. Secondary outcomes included duration of illness, development of severe COVID-19, and adverse reactions. Results There were 157 patients in the intervention and 160 patients in the control group. Characteristics, underlying diseases, and risk factors for severe COVID-19 were comparable in both groups. Improvement in the WHO-category ordinal scale by 2 points was achieved in 98.7% of the intervention group and in 99.4% of the control group (relative risk [RR]: 0.487; 95% confidence interval [CI]: 0.044-5.430). The median illness duration was 5.0 days (range, 3 - 28 days) in intervention group versus 5.2 days (range, 3 - 28 days) in control group (P = 0.630). Severe COVID-19 that required intensive care occurred in 2 patients (1.3%) in the intervention group and 1 patient (0.6%) in the control group (RR: 2.052; 95% CI: 0.184 - 22.857). No significant difference in serious drug adverse events was seen. Conclusion In this study ivermectin plus standard of care was not associated with improvement in the WHO-category ordinal scale, reduced illness duration, or development of severe COVID-19 in moderately ill COVID-19 patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we demonstrate the potential role of VNPP433-3β as molecular glue that induces physical proximity between the Androgen Receptor and MDM2 E3 ligase in prostate cancer cells. The interaction promotes MDM2-mediated ubiquitination of AR and its subsequent proteasomal degradation resulting in growth inhibition of prostate cancer cells. Targeted protein degradation is a fast-evolving therapeutic strategy to target even the traditionally undruggable target proteins. Contrary to the traditional small-molecule inhibitors of enzyme or receptor antagonists that bind the active site pockets in the target protein, molecular glue degraders facilitate interaction of target proteins with E3 ubiquitin ligases by stabilizing the ternary complex and induce physical proximity, thereby triggering ubiquitination and subsequent proteasomal degradation. AR plays a key role in all stages of prostate cancer. It is activated by the binding of androgenic hormones and transcriptionally regulates multiple genes including the ones that regulate cell cycle. Using HiBiT CRISPR cell line, biochemical methods, and RNA sequencing, we report the potential role of VNPP433-3β, the next generation galeterone analog as molecular glue that brings together AR, the key driver of prostate cancer and MDM2, an E3 ubiquitin ligase leading to ubiquitination and subsequent degradation of f-AR and AR-V7 in prostate cancer cells. [ABSTRACT FROM AUTHOR]

Background The coronavirus disease 2019 (COVID-19) pandemic had a considerable impact on US healthcare systems, straining hospital resources, staff, and operations. However, a comprehensive assessment of the impact on healthcare-associated infections (HAIs) across different hospitals with varying level of infectious disease (ID) physician expertise, resources, and infrastructure is lacking. Methods This retrospective longitudinal multicenter cohort study included central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), Clostridioides difficile infections (CDIs), and ventilator-associated events (VAEs) from 53 hospitals (academic and community) in Southeastern United States from 1 January 2018 to 31 March 2021. Segmented negative binomial regression generalized estimating equations models estimated changes in monthly incidence rates in the baseline (01/2018–02/2020) compared to the pandemic period (03/2020–03/2021, further divided into three pandemic phases). Results CLABSIs and VAEs increased by 24% and 34%, respectively, during the pandemic period. VAEs increased in all phases of the pandemic, while CLABSIs increased in later phases of the pandemic. CDI trend increased by 4.2% per month in the pandemic period. On stratifying the analysis by hospital characteristics, the impact of the pandemic on healthcare-associated infections was more significant in smaller sized and community hospitals. CAUTIs did not change significantly during the pandemic across all hospital types. Conclusions CLABSIs, VAEs, and CDIs increased significantly during the pandemic, especially in smaller community hospitals, most of which lack ID physician expertise. Future efforts should focus on better understanding challenges faced by community hospitals, strengthening the infection prevention infrastructure, and expanding the ID workforce, particularly to community hospitals. [ABSTRACT FROM AUTHOR]

The United States varicella vaccination program has successfully reduced varicella incidence and hospitalizations by ≥90%, consequently reducing the risk of nosocomial exposures. However, patients and healthcare personnel (HCP) continue to introduce varicella zoster virus (VZV) into healthcare settings. Herpes zoster (HZ) is less contagious than varicella, but it can also result in exposures. Unrecognized varicella and HZ may lead to extensive contact investigations, control efforts, and HCP furloughs that result in significant disruption of healthcare activities as well as substantial costs. Robust occupational health and infection prevention programs that ensure healthcare personnel immunity and prompt recognition and isolation of patients with varicella or HZ will lower the risk of VZV transmission and reduce or eliminate the need to furlough exposed HCP and associated costs. [ABSTRACT FROM AUTHOR]

Interference, the dependency of an individual's potential outcome on the exposure of other individuals, is a common occurrence in medicine and public health. Recently, targeted maximum likelihood estimation (TMLE) has been extended to settings of interference, including in the context of estimation of the mean of an outcome under a specified distribution of exposure, referred to as a policy. This paper summarizes how TMLE for independent data is extended to general interference (network-TMLE). An extensive simulation study is presented of network-TMLE, consisting of four data generating mechanisms (unit-treatment effect only, spillover effects only, unit-treatment and spillover effects, infection transmission) in networks of varying structures. Simulations show that network-TMLE performs well across scenarios with interference, but issues manifest when policies are not well-supported by the observed data, potentially leading to poor confidence interval coverage. Guidance for practical application, freely available software, and areas of future work are provided. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5′ cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5′cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo. [ABSTRACT FROM AUTHOR]

Background: Early in the pandemic, transmission risk from asymptomatic infection was unclear, making it imperative to monitor infection in workplace settings. Further, data on SARS-CoV-2 seroprevalence within university populations has been limited. Methods: We performed a longitudinal study of University research employees on campus July-December 2020. We conducted questionnaires on COVID-19 risk factors, RT-PCR testing, and SARS-CoV-2 serology using an in-house spike RBD assay, laboratory-based Spike NTD assay, and standard nucleocapsid platform assay. We estimated prevalence and cumulative incidence of seroconversion with 95% confidence intervals using the inverse of the Kaplan-Meier estimator. Results: 910 individuals were included in this analysis. At baseline, 6.2% (95% CI 4.29–8.19) were seropositive using the spike RBD assay; four (0.4%) were seropositive using the nucleocapsid assay, and 44 (4.8%) using the Spike NTD assay. Cumulative incidence was 3.61% (95% CI: 2.04–5.16). Six asymptomatic individuals had positive RT-PCR results. Conclusions: Prevalence and incidence of SARS-CoV-2 infections were low; however, differences in target antigens of serological tests provided different estimates. Future research on appropriate methods of serological testing in unvaccinated and vaccinated populations is needed. Frequent RT-PCR testing of asymptomatic individuals is required to detect acute infections, and repeated serosurveys are beneficial for monitoring subclinical infection. [ABSTRACT FROM AUTHOR]

Background Patients with Clostridioides difficile infections (CDIs) contaminate the healthcare environment; however, the relative contribution of contamination by colonized individuals is unknown. Current guidelines do not recommend the use of contact precautions for asymptomatic C difficile carriers. We evaluated C difficile environmental contamination in rooms housing adult inpatients with diarrhea based on C difficile status. Methods We performed a prospective cohort study of inpatient adults with diarrhea who underwent testing for CDI via polymerase chain reaction (PCR) and enzyme immunoassay (EIA). Patients were stratified into cohorts based on test result: infected (PCR+/EIA+), colonized (PCR+/EIA−), or negative/control (PCR−). Environmental microbiological samples were taken within 24 hours of C difficile testing and again for 2 successive days. Samples were obtained from the patient, bathroom, and care areas. Results We enrolled 94 patients between November 2019 and June 2021. Clostridioides difficile was recovered in 93 (38%) patient rooms: 44 (62%) infected patient rooms, 35 (43%) colonized patient rooms (P  = .08 vs infected 38 patient rooms), and 14 (15%) negative patient rooms (P  < .01 vs infected; P  < .01 vs colonized). Clostridioides difficile was recovered in 40 (56%), 6 (9%), and 20 (28%) of bathrooms, care areas and patient areas in 40 infected patient rooms; 34 (41%), 1 (1%), and 4 (5%) samples in colonized patient rooms; and 12 (13%), 1 (1%), and 3 (3%) of samples in negative patient rooms, respectively. Conclusions Patients colonized with C difficile frequently contaminated the hospital environment. Our data support the use of contact precautions when entering rooms of patients colonized with C difficile , especially when entering the bathroom. [ABSTRACT FROM AUTHOR]

Individuals treated with dialysis are at high risk for healthcare-associated infections. We conducted a literature review of outbreaks associated with water in hemodialysis during years 2011–2021 to understand the role of water as a source of infections for patients receiving hemodialysis with a focus on the risks associated with dialysis water and dialysate. For dialysis patients, water and dialysate have been a source of healthcare-associated pathogens, including nontuberculous mycobacteria and gram-negative bacilli as well as systemic reactions due to gram-negative bacilli–associated endotoxin. Lapses in infection prevention practices and dialysis water management were primarily involved in waterborne outbreaks. Dialysis clinics should adhere to recommendations regarding monitoring and levels of bacteria and endotoxin in hemodialysis water and dialysate. Since hemodialysis patients are at increased risk of healthcare-associated infections, it is important for healthcare personnel to adhere to infection prevention guidelines in hemodialysis patient care, especially hand hygiene, aseptic technique, cleaning/disinfection, and water management. [ABSTRACT FROM AUTHOR]

Background Shedding of Clostridioides difficile spores from infected individuals contaminates the hospital environment and contributes to infection transmission. We assessed whether antibiotic selection affects C. difficile shedding and contamination of the hospital environment. Methods In this prospective, unblinded, randomized controlled trial of hospitalized adults with C. difficile infection, patients were randomized 1:1:1 to receive fidaxomicin, oral vancomycin, or metronidazole. The primary outcome was change in environmental contamination rate during treatment. Secondary outcomes included stool shedding, total burden of contamination, and molecular relatedness of stool versus environmental C. difficile isolates. Results Of 33 patients enrolled, 31 (94%) completed the study. Fidaxomicin (−0.36 log10 colony-forming units [CFUs]/d [95% confidence interval (CI), −.52 to −.19]; P  < .01) and vancomycin (−0.17 log10 CFUs/d [−.34 to −.01]; P  = .05) were associated with more rapid decline in C. difficile shedding than metronidazole (−0.01 log10 CFUs/d [95% CI, −.10 to.08). Both vancomycin (6.3% [95% CI, 4.7–8.3) and fidaxomicin (13.1% [10.7–15.9]) were associated with lower rates of environmental contamination than metronidazole (21.4% [18.0–25.2]). With specific modeling of within-subject change over time, fidaxomicin (adjusted odds ratio, 0.83 [95% CI,.70–.99]; P  = .04) was associated with more rapid decline in environmental contamination than vancomycin or metronidazole. Overall, 207 of 233 environmental C. difficile isolates (88.8%) matched patient stool isolates by ribotyping, without significant difference by treatment. Conclusions Fidaxomicin, and to a lesser extent vancomycin, reduces C. difficile shedding and contamination of the hospital environment relative to metronidazole. Treatment choice may play a role in reducing healthcare-associated C. difficile transmission. Clinical Trials Registration NCT02057198. [ABSTRACT FROM AUTHOR]

Introduction: Symptoms associated with SARS-CoV-2 infection remain incompletely understood, especially among ambulatory, non-hospitalized individuals. With host factors, symptoms predictive of SARS-CoV-2 could be used to guide testing and intervention strategies. Methods: Between March 16 and September 3, 2020, we examined the characteristics and symptoms reported by individuals presenting to a large outpatient testing program in the Southeastern US for nasopharyngeal SARS-CoV-2 RNA RT-PCR testing. Using self-reported symptoms, demographic characteristics, and exposure and travel histories, we identified the variables associated with testing positive using modified Poisson regression. Results: Among 20,177 tested individuals, the proportion positive was 9.4% (95% CI, 9.0–9.8) and was higher for men, younger individuals, and racial/ethnic minorities (all P<0.05); the positivity proportion was higher for Hispanics (26.9%; 95% CI. 24.9–29.0) compared to Blacks (8.6%; 95% CI, 7.6–9.7) or Whites (5.8%; 95% CI, 5.4–6.3). Individuals reporting contact with a COVID-19 case had the highest positivity proportion (22.8%; 95% CI, 21.5–24.1). Among the subset of 8,522 symptomatic adults who presented for testing after May 1, when complete symptom assessments were performed, SARS-CoV-2 RNA PCR was detected in 1,116 (13.1%). Of the reported symptoms, loss of taste or smell was most strongly associated with SARS-CoV-2 RNA detection with an adjusted risk ratio of 3.88 (95% CI, 3.46–4.35). The presence of chills, fever, cough, aches, headache, fatigue and nasal congestion also significantly increased the risk of detecting SARS-CoV-2 RNA, while diarrhea or nausea/vomiting, although not uncommon, were significantly more common in those with a negative test result. Symptom combinations were frequent with 67.9% experiencing ≥4 symptoms, including 19.8% with ≥8 symptoms; report of greater than three symptoms increased the risk of SARS-CoV-2 RNA detection. Conclusions: In a large outpatient population in the Southeastern US, several symptoms, most notably loss of taste or smell, and greater symptom burden were associated with detection of SARS-CoV-2 RNA. Persons of color and those with who were a contact of a COVID-19 case were also more likely to test positive. These findings suggest that, given limited SARS-CoV-2 testing capacity, symptom presentation and host characteristics can be used to guide testing and intervention prioritization. [ABSTRACT FROM AUTHOR]

SET (TAF-1β/I2PP2A) is a ubiquitously expressed, multifunctional protein that plays a role in regulating diverse cellular processes, including cell cycle progression, migration, apoptosis, transcription, and DNA repair. SET expression is ubiquitous across all cell types. However, it is overexpressed or post-translationally modified in several solid tumors and blood cancers, where expression levels are correlated with worsening clinical outcomes. SET exerts its oncogenic effects primarily through the formation of antagonistic protein complexes with the tumor suppressor, protein phosphatase 2A (PP2A), and the well-known metastasis suppressor, nm23-H1. PP2A inhibition is often observed as a secondary driver of tumorigenesis and metastasis in human cancers. Preclinical studies have shown that the pharmacological reactivation of PP2A combined with potent inhibitors of the primary driver oncogene produces synergistic cell death and decreased drug resistance. Therefore, the development of novel inhibitors of the SET-PP2A interaction presents an attractive approach to reactivation of PP2A, and thereby, tumor suppression. NMR provides a unique platform to investigate protein targets in their natively folded state to identify protein and small-molecule ligands and report on the protein internal dynamics. The backbone 1HN, 13C, and 15N NMR resonance assignments were completed for the 204 amino acid nucleosome assembly protein-1 (NAP-1) domain of the human SET oncoprotein (residues 23–225). These assignments provide a vital first step toward the development of novel PP2A reactivators via SET-selective inhibition. [ABSTRACT FROM AUTHOR]

S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3. [ABSTRACT FROM AUTHOR]

The taro plant, Colocasia esculenta, contains bioactive proteins with potential as cancer therapeutics. Several groups have reported anti-cancer activity in vitro and in vivo of taro-derived extracts (TEs). We reported that TE inhibits metastasis in a syngeneic murine model of Triple-Negative Breast Cancer (TNBC). Purpose: We sought to confirm our earlier studies in additional models and to identify novel mechanisms by which efficacy is achieved. Methods: We employed a panel of murine and human breast and ovarian cancer cell lines to determine the effect of TE on tumor cell viability, migration, and the ability to support cancer stem cells. Two syngeneic models of TNBC were employed to confirm our earlier report that TE potently inhibits metastasis. Cancer stem cell assays were employed to determine the ability of TE to inhibit tumorsphere-forming ability and to inhibit aldehyde dehydrogenase activity. To determine if host immunity contributes to the mechanism of metastasis inhibition, efficacy was assessed in immune-compromised mice. Results: We demonstrate that viability of some, but not all cell lines is inhibited by TE. Likewise, tumor cell migration is inhibited by TE. Using 2 immune competent, syngeneic models of TNBC, we confirm our earlier findings that tumor metastasis is potently inhibited by TE. We also demonstrate, for the first time, that TE directly inhibits breast cancer stem cells. Administration of TE to mice elicits expansion of several spleen cell populations but it was not known if host immune cells contribute to the mechanism by which TE inhibits tumor cell dissemination. In novel findings, we now show that the ability of TE to inhibit metastasis relies on immune T-cell-dependent, but not B cell or Natural Killer (NK)-cell-dependent mechanisms. Thus, both tumor cell-autonomous and host immune factors contribute to the mechanisms underlying TE efficacy. Our long-term goal is to evaluate TE efficacy in clinical trials. Most of our past studies as well as many of the results reported in this report were carried out using an isolation protocol described earlier (TE). In preparation for a near future clinical trial, we have now developed a strategy to isolate an enriched taro fraction, TE-method 2, (TE-M2) as well as a more purified subfraction (TE-M2F1) which can be scaled up under Good Manufacturing Practice (GMP) conditions for evaluation in human subjects. We demonstrate that TE-M2 and TE-M2F1 retain the anti-metastatic properties of TE. Conclusions: These studies provide further support for the continued examination of biologically active components of Colocasia esculenta as potential new therapeutic entities and identify a method to isolate sufficient quantities under GMP conditions to conduct early phase clinical studies. [ABSTRACT FROM AUTHOR]

The healthcare environment serves as one of the possible routes of transmission of epidemiologically important pathogens, but the role of the contaminated environment on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission remains unclear. We reviewed survival, contamination, and transmission of SARS-CoV-2 via environmental surfaces and shared medical devices as well as environmental disinfection of SARS-CoV-2 in healthcare settings. Coronaviruses, including SARS-CoV-2, have been demonstrated to survive for hours to days on environmental surfaces depending on experimental conditions. The healthcare environment is frequently contaminated with SARS-CoV-2 RNA in most studies but without evidence of viable virus. Although direct exposure to respiratory droplets is the main transmission route of SARS-CoV-2, the contaminated healthcare environment can potentially result in transmission of SARS-CoV-2 as described with other coronaviruses such as SARS and Middle East respiratory syndrome coronaviruses. It is important to improve thoroughness of cleaning/disinfection practices in healthcare facilities and select effective disinfectants to decontaminate inanimate surfaces and shared patient care items. [ABSTRACT FROM AUTHOR]

We assessed environmental contamination of inpatient rooms housing coronavirus disease 2019 (COVID-19) patients in a dedicated COVID-19 unit. Contamination with severe acute respiratory syndrome coronavirus 2 was found on 5.5% (19/347) of surfaces via reverse transcriptase polymerase chain reaction and 0.3% (1/347) of surfaces via cell culture. Environmental contamination is uncommon in hospitals rooms; RNA presence is not a specific indicator of infectious virus. [ABSTRACT FROM AUTHOR]

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Clostridioides difficile is a bacterial pathogen responsible for the majority of nosocomial infections in the developed world. C. difficile infection (CDI) is difficult to treat in many cases because hypervirulent strains have evolved that contain a third toxin, termed the C. difficile toxin (CDT), in addition to the two enterotoxins TcdA and TcdB. CDT is a binary toxin comprised of an enzymatic, ADP-ribosyltransferase (ART) toxin component, CDTa, and a pore-forming or delivery subunit, CDTb. In the absence of CDTa, CDTb assembles into two distinct di-heptameric states, a symmetric and an asymmetric form with both states having two surface-accessible host cell receptor-binding domains, termed RBD1 and RBD2. RBD1 has a unique amino acid sequence, when aligned to other well-studied binary toxins (i.e., anthrax), and it contains a novel Ca2+-binding site important for CDTb stability. The other receptor binding domain, RBD2, is critically important for CDT toxicity, and a domain such as this is missing altogether in other binary toxins and shows further that CDT is unique when compared to other binary toxins. In this study, the 1H, 13C, and 15N backbone and sidechain resonances of the 120 amino acid RBD2 domain of CDTb (residues 757–876) were assigned sequence-specifically and provide a framework for future NMR-based drug discovery studies directed towards targeting the most virulent strains of CDI. [ABSTRACT FROM AUTHOR]

We describe the design, kinetic properties, and structures of engineered subtilisin proteases that degrade the active form of RAS by cleaving a conserved sequence in switch 2. RAS is a signaling protein that, when mutated, drives a third of human cancers. To generate high specificity for the RAS target sequence, the active site was modified to be dependent on a cofactor (imidazole or nitrite) and protease sub-sites were engineered to create a linkage between substrate and cofactor binding. Selective proteolysis of active RAS arises from a 2-step process wherein sub-site interactions promote productive binding of the cofactor, enabling cleavage. Proteases engineered in this way specifically cleave active RAS in vitro, deplete the level of RAS in a bacterial reporter system, and also degrade RAS in human cell culture. Although these proteases target active RAS, the underlying design principles are fundamental and will be adaptable to many target proteins. Chen et al. describe a rational design of subtilisin mutants that degrade active RAS by cleaving a conserved sequence in switch 2. They further modified the active site to be dependent on a cofactor to generate high target specificity. Proteases engineered to cleave this region degraded RAS in vitro and in cells with a promise of adaptability for other target proteins too. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the association between rates of methicillin-resistant Staphylococcus aureus (MRSA)/Clostridioides difficile and quality and clinical outcomes in US acute care hospitals. The population was all Medicare-certified US acute care hospitals with MRSA/C difficile standardized infection ratio (SIR) data available from 2013 to 2017. Hospital-level data from the Centers for Medicare & Medicaid Services were used to estimate hospital and time fixed effects models for 30-day hospital readmissions, length of stay, 30-day mortality, and days in the intensive care unit. The key explanatory variables were SIR for MRSA and C difficile. No association was found between MRSA or C difficile rates and any of the 4 outcomes. The null results add to the mixed evidence in the field, but there are likely residual confounding factors. Future research should use larger samples of patient-level data and appropriate methods to provide evidence to guide efforts to tackle antimicrobial resistance. [ABSTRACT FROM AUTHOR]

We examined the microbial burden on hospital room environmental sites after standard (quaternary ammonium [Quat]) or enhanced disinfection (quat/ultraviolet light [UV-C], bleach, or bleach/UV-C). An enhanced terminal room disinfection reduced the microbial burden of epidemiologically important pathogens on high-touch surfaces in patient rooms, especially sites around the bed, better than standard room disinfection. [ABSTRACT FROM AUTHOR]

The taro plant, Colocasia esculenta, contains bioactive proteins with potential as cancer therapeutics. Several groups have reported anti-cancer activity in vitro and in vivo of taro-derived extracts (TEs). We reported that TE inhibits metastasis in a syngeneic murine model of Triple-Negative Breast Cancer (TNBC). Purpose: We sought to confirm our earlier studies in additional models and to identify novel mechanisms by which efficacy is achieved. Methods: We employed a panel of murine and human breast and ovarian cancer cell lines to determine the effect of TE on tumor cell viability, migration, and the ability to support cancer stem cells. Two syngeneic models of TNBC were employed to confirm our earlier report that TE potently inhibits metastasis. Cancer stem cell assays were employed to determine the ability of TE to inhibit tumorsphere-forming ability and to inhibit aldehyde dehydrogenase activity. To determine if host immunity contributes to the mechanism of metastasis inhibition, efficacy was assessed in immune-compromised mice. Results: We demonstrate that viability of some, but not all cell lines is inhibited by TE. Likewise, tumor cell migration is inhibited by TE. Using 2 immune competent, syngeneic models of TNBC, we confirm our earlier findings that tumor metastasis is potently inhibited by TE. We also demonstrate, for the first time, that TE directly inhibits breast cancer stem cells. Administration of TE to mice elicits expansion of several spleen cell populations but it was not known if host immune cells contribute to the mechanism by which TE inhibits tumor cell dissemination. In novel findings, we now show that the ability of TE to inhibit metastasis relies on immune T-cell-dependent, but not B cell or Natural Killer (NK)-cell-dependent mechanisms. Thus, both tumor cell-autonomous and host immune factors contribute to the mechanisms underlying TE efficacy. Our long-term goal is to evaluate TE efficacy in clinical trials. Most of our past studies as well as many of the results reported in this report were carried out using an isolation protocol described earlier (TE). In preparation for a near future clinical trial, we have now developed a strategy to isolate an enriched taro fraction, TE-method 2, (TE-M2) as well as a more purified subfraction (TE-M2F1) which can be scaled up under Good Manufacturing Practice (GMP) conditions for evaluation in human subjects. We demonstrate that TE-M2 and TE-M2F1 retain the anti-metastatic properties of TE. Conclusions: These studies provide further support for the continued examination of biologically active components of Colocasia esculenta as potential new therapeutic entities and identify a method to isolate sufficient quantities under GMP conditions to conduct early phase clinical studies. [ABSTRACT FROM AUTHOR]