The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.

One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Within-host evolutionary dynamics and tissue compartmentalization during acute SARS-CoV-2 infection.

The global evolution of SARS-CoV-2 depends in part upon the evolutionary dynamics within individual hosts with varying immune histories. To characterize the within-host evolution of acute SARS-CoV-2 infection, we sequenced saliva and nasal samples collected daily from vaccinated and unvaccinated individuals early during infection. We show that longitudinal sampling facilitates high-confidence genetic variant detection and reveals evolutionary dynamics missed by less-frequent sampling strategies. Within-host dynamics in both unvaccinated and vaccinated individuals appeared largely stochastic; however, in rare cases, minor genetic variants emerged to frequencies sufficient for forward transmission. Finally, we detected significant genetic compartmentalization of viral variants between saliva and nasal swab sample sites in many individuals. Altogether, these data provide a high-resolution profile of within-host SARS-CoV-2 evolutionary dynamics.IMPORTANCEWe detail the within-host evolutionary dynamics of SARS-CoV-2 during acute infection in 31 individuals using daily longitudinal sampling. We characterized patterns of mutational accumulation for unvaccinated and vaccinated individuals, and observed that temporal variant dynamics in both groups were largely stochastic. Comparison of paired nasal and saliva samples also revealed significant genetic compartmentalization between tissue environments in multiple individuals. Our results demonstrate how selection, genetic drift, and spatial compartmentalization all play important roles in shaping the within-host evolution of SARS-CoV-2 populations during acute infection.

Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study.

BACKGROUND: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. OBJECTIVE: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. DESIGN: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. SETTING: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. PARTICIPANTS: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. MEASUREMENTS: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. RESULTS: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. LIMITATION: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. CONCLUSION: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. PRIMARY FUNDING SOURCE: National Institutes of Health RADx Tech program.

Reduced perceptual narrowing in synesthesia.

Synesthesia is a neurologic trait in which specific inducers, such as sounds, automatically elicit additional idiosyncratic percepts, such as color (thus "colored hearing"). One explanation for this trait-and the one tested here-is that synesthesia results from unusually weak pruning of cortical synaptic hyperconnectivity during early perceptual development. We tested the prediction from this hypothesis that synesthetes would be superior at making discriminations from nonnative categories that are normally weakened by experience-dependent pruning during a critical period early in development-namely, discrimination among nonnative phonemes (Hindi retroflex /d̪a/ and dental /ɖa/), among chimpanzee faces, and among inverted human faces. Like the superiority of 6-mo-old infants over older infants, the synesthetic groups were significantly better than control groups at making all the nonnative discriminations across five samples and three testing sites. The consistent superiority of the synesthetic groups in making discriminations that are normally eliminated during infancy suggests that residual cortical connectivity in synesthesia supports changes in perception that extend beyond the specific synesthetic percepts, consistent with the incomplete pruning hypothesis.

Comparison of Rapid Antigen Tests' Performance Between Delta and Omicron Variants of SARS-CoV-2 : A Secondary Analysis From a Serial Home Self-testing Study.

BACKGROUND: It is important to document the performance of rapid antigen tests (Ag-RDTs) in detecting SARS-CoV-2 variants. OBJECTIVE: To compare the performance of Ag-RDTs in detecting the Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2. DESIGN: Secondary analysis of a prospective cohort study that enrolled participants between 18 October 2021 and 24 January 2022. Participants did Ag-RDTs and collected samples for reverse transcriptase polymerase chain reaction (RT-PCR) testing every 48 hours for 15 days. SETTING: The parent study enrolled participants throughout the mainland United States through a digital platform. All participants self-collected anterior nasal swabs for rapid antigen testing and RT-PCR testing. All Ag-RDTs were completed at home, whereas nasal swabs for RT-PCR were shipped to a central laboratory. PARTICIPANTS: Of 7349 participants enrolled in the parent study, 5779 asymptomatic persons who tested negative for SARS-CoV-2 on day 1 of the study were eligible for this substudy. MEASUREMENTS: Sensitivity of Ag-RDTs on the same day as the first positive (index) RT-PCR result and 48 hours after the first positive RT-PCR result. RESULTS: A total of 207 participants were positive on RT-PCR (58 Delta, 149 Omicron). Differences in sensitivity between variants were not statistically significant (same day: Delta, 15.5% [95% CI, 6.2% to 24.8%] vs. Omicron, 22.1% [CI, 15.5% to 28.8%]; at 48 hours: Delta, 44.8% [CI, 32.0% to 57.6%] vs. Omicron, 49.7% [CI, 41.6% to 57.6%]). Among 109 participants who had RT-PCR-positive results for 48 hours, rapid antigen sensitivity did not differ significantly between Delta- and Omicron-infected participants (48-hour sensitivity: Delta, 81.5% [CI, 66.8% to 96.1%] vs. Omicron, 78.0% [CI, 69.1% to 87.0%]). Only 7.2% of the 69 participants with RT-PCR-positive results for shorter than 48 hours tested positive by Ag-RDT within 1 week; those with Delta infections remained consistently negative on Ag-RDTs. LIMITATION: A testing frequency of 48 hours does not allow a finer temporal resolution of the analysis of test performance, and the results of Ag-RDTs are based on self-report. CONCLUSION: The performance of Ag-RDTs in persons infected with the SARS-CoV-2 Omicron variant is not inferior to that in persons with Delta infections. Serial testing improved the sensitivity of Ag-RDTs for both variants. The performance of rapid antigen testing varies on the basis of duration of RT-PCR positivity. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Limitations of Molecular and Antigen Test Performance for SARS-CoV-2 in Symptomatic and Asymptomatic COVID-19 Contacts.

COVID-19 has brought unprecedented attention to the crucial role of diagnostics in pandemic control. We compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test performance by sample type and modality in close contacts of SARS-CoV-2 cases. Close contacts of SARS-CoV-2-positive individuals were enrolled after informed consent. Clinician-collected nasopharyngeal (NP) swabs in viral transport media (VTM) were tested with a routine clinical reference nucleic acid test (NAT) and PerkinElmer real-time reverse transcription-PCR (RT-PCR) assay; positive samples were tested for infectivity using a VeroE6TMPRSS2 cell culture model. Self-collected passive drool was also tested using the PerkinElmer RT-PCR assay. For the first 4 months of study, midturbinate swabs were tested using the BD Veritor rapid antigen test. Between 17 November 2020 and 1 October 2021, 235 close contacts of SARS-CoV-2 cases were recruited, including 95 with symptoms (82% symptomatic for ≤5 days) and 140 asymptomatic individuals. Reference NATs were positive for 53 (22.6%) participants; 24/50 (48%) were culture positive. PerkinElmer testing of NP and saliva samples identified an additional 28 (11.9%) SARS-CoV-2 cases who tested negative by reference NAT. Antigen tests performed for 99 close contacts showed 83% positive percent agreement (PPA) with reference NAT among early symptomatic persons, but 18% PPA in others; antigen tests in 8 of 11 (72.7%) culture-positive participants were positive. Contacts of SARS-CoV-2 cases may be falsely negative early after contact, but more sensitive platforms may identify these cases. Repeat or serial SARS-CoV-2 testing with both antigen and molecular assays may be warranted for individuals with high pretest probability for infection.

Purchases of Nontaxed Foods, Beverages, and Alcohol in a Longitudinal Cohort After Implementation of the Philadelphia Beverage Tax.

BACKGROUND: Evidence suggests that sweetened beverage taxes reduce taxed beverage purchases, but few studies have used individual-level data to assess whether these taxes affect purchases of nontaxed foods, beverages, and alcohol. Additionally, research has not examined whether sweetened beverage taxes influence restaurant purchases. OBJECTIVES: We assessed changes in individuals' purchases of taxed beverage types; low-calorie/low-added-sugar nontaxed beverages; high-calorie/high-added-sugar nontaxed beverages, foods, and alcohol; and beverages from restaurants following implementation of the 1.5 cent-per-ounce Philadelphia sweetened beverage tax. METHODS: A longitudinal cohort of adult sugar-sweetened beverage consumers in Philadelphia (n = 306; 67% female; mean age: 43.9 years) and Baltimore (n = 297; comparison city without a beverage tax; 58% female; mean age: 41.7 years) submitted all food and beverage receipts during 2-week periods at baseline and at 3, 6, and 12 months posttax. Difference-in-differences analyses compared changes in purchases from pre- to posttax in Philadelphia to changes in Baltimore. RESULTS: Purchases of taxed juice drinks [ratio of incidence rate ratios (RIRR) = 0.62; 95% CI, 0.42-0.91], but not other taxed beverage types, decreased in Philadelphia compared to Baltimore following the tax. Analyses did not find changes in purchases of low-calorie/low-added-sugar nontaxed beverages, such as water or milk. Additionally, analyses did not find increases in purchases of most high-calorie/high-added-sugar nontaxed products, including alcohol, juice, candy, sweet snacks, salty snacks, and desserts. Purchases of beverage concentrates increased in Philadelphia (RIRR = 2.22; 95% CI, 1.39-3.54). CONCLUSIONS: In this difference-in-differences analysis, the Philadelphia beverage tax was associated with reduced purchases of taxed juice drinks. Purchases of beverage concentrates increased after the tax, but no increases were observed for other high-calorie/high-added-sugar nontaxed foods, beverages, or alcohol.

Do Longitudinal Trends in Tobacco 21-Related Media Coverage Correlate with Policy Support? an Exploratory Analysis Using Supervised and Unsupervised Machine Learning Methods.

Media coverage can impact support for health policies and, ultimately, compliance with those policies. Prior research found consistent, high support for Tobacco 21 policies, which raise the minimum legal age of tobacco purchase to 21, among adults and nonsmoking youth. However, a recent study found support (i.e., agreement with the statement: "The legal age to buy tobacco cigarettes should be increased from 18 to 21") among 13-20-year-old smokers increased from 2014 until mid-2016 and then declined steadily through mid-2017. To assess whether media coverage could be related to young smokers' changing support, we conducted an exploratory content analysis to identify texts about Tobacco 21 in a large corpus of tobacco texts (N = 135,691) published in four popular media sources from 2014 to 2017. For this content analysis, we developed a novel methodological approach that combined supervised and unsupervised machine learning methods and could be useful in other areas of communication research. We found that the prevalence of Tobacco 21 media coverage and Tobacco 21 support among young smokers exhibited similar temporal patterns for much of the study period. These findings highlight the need for continued research into the effects of media coverage on Tobacco 21 support among young smokers, a group that must comply with Tobacco 21 policies in order to ensure maximum effectiveness. This research is of particular utility following the 2019 passage of a federal Tobacco 21 regulation, as the public health impact of this regulation could be limited by low public support, and thus low rates of policy compliance.

Longitudinal Assessment of Diagnostic Test Performance Over the Course of Acute SARS-CoV-2 Infection.

BACKGROUND: Serial screening is critical for restricting spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by facilitating timely identification of infected individuals to interrupt transmission. Variation in sensitivity of different diagnostic tests at different stages of infection has not been well documented. METHODS: In a longitudinal study of 43 adults newly infected with SARS-CoV-2, all provided daily saliva and nasal swabs for quantitative reverse transcription polymerase chain reaction (RT-qPCR), Quidel SARS Sofia antigen fluorescent immunoassay (FIA), and live virus culture. RESULTS: Both RT-qPCR and Quidel SARS Sofia antigen FIA peaked in sensitivity during the period in which live virus was detected in nasal swabs, but sensitivity of RT-qPCR tests rose more rapidly prior to this period. We also found that serial testing multiple times per week increases the sensitivity of antigen tests. CONCLUSIONS: RT-qPCR tests are more effective than antigen tests at identifying infected individuals prior to or early during the infectious period and thus for minimizing forward transmission (given timely results reporting). All tests showed >98% sensitivity for identifying infected individuals if used at least every 3 days. Daily screening using antigen tests can achieve approximately 90% sensitivity for identifying infected individuals while they are viral culture positive.

Rating the Valence of Media Content about Electronic Cigarettes Using Crowdsourcing: Testing Rater Instructions and Estimating the Optimal Number of Raters.

Electronic cigarettes (e-cigarettes) are a controversial public health topic due to their increasing popularity among youth and the uncertainty about their risks and benefits. Researchers have started to assess the valence of media content about e-cigarette use, mostly using expert coding. The current study aims to offer a methodological framework and guideline when using crowdsourcing to rate the valence of e-cigarette media content. Specifically, we present (1) an experiment to determine rating instructions that would result in reliable valence ratings and (2) an analysis to identify the optimal number of raters needed to replicate these ratings. Specifically, we compared ratings produced by crowdsourced raters instructed to rate from several different perspectives (e.g., objective vs. subjective) and determined the instructions that led to reliable ratings. We then used bootstrapping methods and a set of criteria to identify the minimum number of raters needed to replicate these ratings. Results suggested that when rating e-cigarette valence, instructing raters to rate from their own subjective perspective produced reliable results, and nine raters were deemed the optimal number of raters. We expect these findings to inform future content analyses of e-cigarette valence. The study procedures can be applied to crowdsourced content analyses of other health-related media content to determine appropriate rating instructions and the number of raters.

Candida auris outbreak involving liver transplant recipients in a surgical intensive care unit.

Candida auris is a yeast that is difficult to eradicate and has caused outbreaks in health care facilities. We report a cluster of 5 patients in 1 intensive care unit who were colonized or infected in 2017. The initial 2 patients were recipients of liver transplants who had cultures that grew C auris within 3 days of each other in June 2017 (days 43 and 30 posttransplant). Subsequent screening cultures identified 2 additional patients with C auris colonization. Respiratory and urine cultures from a fifth patient yielded C auris. All isolates were fluconazole resistant but susceptible to echinocandins. Whole genome sequencing showed the strains were clonal, suggesting in-hospital transmission, and related but distinct from New York/New Jersey strains, consistent with a separate introduction. However, no source or contact was found. Two of the 5 patients died. C auris infection likely contributed to 1 patient death by infecting a vascular aneurysm at the graft anastomosis. Strict infection control precautions were initiated to control the outbreak. Our experience reveals that although severe disease from C auris can occur in transplant recipients, outbreaks can be controlled using recommended infection control practices. We have had no further patients infected with C auris to date.

A structured genetics rotation for pediatric residents: an important educational opportunity.

PURPOSE: As the integral role of genetics in health and disease becomes increasingly understood, pediatricians must incorporate genetic principles into their care of patients. Structured exposure to genetics during residency may better equip future pediatricians to meet this goal. METHODS: Pediatric interns in the Johns Hopkins pediatric residency program have the option to spend one week immersed in clinical genetics by attending outpatient clinics and seeing inpatient consults. A pretest assessing clinical genetics knowledge is given before the rotation and compared with an identical post-test. Interns have a "scavenger hunt" to introduce genetic resources useful to pediatricians and complete a logbook of patient experiences. An evaluation is completed at the end of the rotation. RESULTS: Since the selective started in July 2016, 50 interns have participated. Average pretest score was 2.5/5 compared with a post-test score of 4.3/5, p < 0.0001. Interns saw on average ten patients and four different diagnoses. Overall evaluation was 4.4 on a 5-point scale, 5 being "excellent." CONCLUSION: This experience suggests that a structured rotation in genetics provides pediatric interns with an opportunity to learn basic clinical genetics knowledge and skills and see patients whom they may otherwise not encounter during residency.

Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment.

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

Valence of Media Coverage About Electronic Cigarettes and Other Tobacco Products From 2014 to 2017: Evidence From Automated Content Analysis.

INTRODUCTION: As media exposure can influence people's opinions and perceptions about vaping and smoking, analyzing the valence of media content about tobacco products (ie, overall attitude toward tobacco, cigars, electronic cigarettes, etc.) is an important issue. This study advances the field by analyzing a large amount of media content about multiple tobacco products across six different media sources. AIMS AND METHODS: From May 2014 to December 2017, we collected all English-language media items about tobacco products that U.S. young people might see from mass media and websites (long-form) and social media (Twitter and YouTube). We used supervised machine learning to develop validated algorithms to label the valence of these media items. Using the labeled results, we examined the impact of product type (e-cigarettes vs. other tobacco products), source (long-form vs. social media), and time (by month) on the valence of coverage. RESULTS: We obtained 152 886 long-form media texts (20% with more than a passing mention), nearly 86 million tweets, and 12 262 YouTube videos about tobacco products. Most long-form media content opposed, while most social media coverage supported, the use of e-cigarettes and other tobacco products. Over time, within-source valence proportions were stable, though in aggregate, the amount of media coverage against the use of tobacco products decreased. CONCLUSIONS: This study describes the U.S. public communication environment about vaping and smoking for young people and offers a novel big data approach to analyzing media content. Results suggest that content has gradually become less negative toward the use of e-cigarettes and other tobacco products. IMPLICATIONS: This study is the first to examine how the valence of media coverage differs for e-cigarettes versus other tobacco products, across several media sources, and over time using a large corpus of media items. Unlike prior studies, these data allow us to draw conclusions about relative support and opposition for these two categories of products in a variety of media coverage because the same coding scheme was used across products and media sources.

Breadth of Media Scanning Leads to Vaping among Youth and Young Adults: Evidence of Direct and Indirect Pathways from a National Longitudinal Survey.

Electronic cigarette use among youth and young adults has reached an epidemic proportion of growth. This study examined the direct and indirect effects of the breadth of media scanning about e-cigarette use on subsequent vaping behavior through interpersonal communication and changes in descriptive norm perceptions. We conducted a nationally representative longitudinal phone survey of 13- to 25-year-olds from June 2014 to March 2017, with 11,013 respondents who completed a baseline survey, among which 3,212 completed a follow-up 6 months later. The results from both cross-sectional and lagged analyses provided robust evidence to suggest that passive routine exposure to e-cigarette use content from more media outlets predicted increased likelihood of vaping among youth and young adults. High scanners were about twice as likely to vape as non-scanners (17% versus 9%). Mediation models using bootstrapping procedures found that breadth of scanning predicted higher descriptive norm perceptions which were associated with subsequent vaping; in addition, interpersonal communication mediated the relationship between breadth of scanning and changes in descriptive norm perceptions. These findings highlight the important roles of scanning, norm perceptions and interpersonal discussions in shaping cognition and behavior changes. The results also suggest an overall pro-e-cigarette public communication environment, which warrants further examination.

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC50 value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1-induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

A framework for assessing the lifetime economic burden of congenital cytomegalovirus in the United States.

BACKGROUND: In the United States (US), congenital cytomegalovirus infection (cCMVi) is a major cause of permanent disabilities and the most common etiology of non-genetic sensorineural hearing loss. Evaluations of prevention strategies will require estimates of the economic implications of cCMVi. We aimed to develop a conceptual framework to characterize the lifetime economic burden of cCMVi in the US and to use that framework to identify data gaps. METHODS: Direct health care, direct non-health care, indirect, and intangible costs associated with cCMVi were considered. An initial framework was constructed based on a targeted literature review, then validated and refined after consultation with experts. Published costs were identified and used to populate the framework. Data gaps were identified. RESULTS: The framework was constructed as a chance tree, categorizing clinical event occurrence to form patient profiles associated with distinct economic trajectories. The distribution and magnitude of costs varied by patient life stage, cCMVi diagnosis, severity of impairment, and developmental delays/disabilities. Published studies could not fully populate the framework. The literature best characterized direct health care costs associated with the birth period. Gaps existed for direct non-health care, indirect, and intangible costs, as well as health care costs associated with adult patients and those severely impaired. CONCLUSIONS: Data gaps exist concerning the lifetime economic burden of cCMVi in the US. The conceptual framework provides the basis for a research agenda to address these gaps. Understanding the full lifetime economic burden of cCMVi would inform clinicians, researchers, and policymakers, when assessing the value of cCMVi interventions.

Combining Crowd-Sourcing and Automated Content Methods to Improve Estimates of Overall Media Coverage: Theme Mentions in E-cigarette and Other Tobacco Coverage.

Exposure to media content can shape public opinions about tobacco. Accurately describing content is a first step to showing such effects. Historically, content analyses have hand-coded tobacco-focused texts from a few media sources which ignored passing mention coverage and social media sources, and could not reliably capture over-time variation. By using a combination of crowd-sourced and automated coding, we labeled the population of all e-cigarette and other tobacco-related (including cigarettes, hookah, cigars, etc.) 'long-form texts' (focused and passing coverage, in mass media and website articles) and social media items (tweets and YouTube videos) collected May 2014-June 2017 for four tobacco control themes. Automated coding of theme coverage met thresholds for item-level precision and recall, event validation, and weekly-level reliability for most sources, except YouTube. Health, Policy, Addiction and Youth themes were frequent in e-cigarette long-form focused coverage (44%-68%), but not in long-form passing coverage (5%-22%). These themes were less frequent in other tobacco coverage (long-form focused (13-32%) and passing coverage (4-11%)). Themes were infrequent in both e-cigarette (1-3%) and other tobacco tweets (2-4%). Findings demonstrate that passing e-cigarette and other tobacco long-form coverage and social media sources paint different pictures of theme coverage than focused long-form coverage. Automated coding also allowed us to code the amount of data required to estimate reliable weekly theme coverage over three years. E-cigarette theme coverage showed much more week-to-week variation than did other tobacco coverage. Automated coding allows accurate descriptions of theme coverage in passing mentions, social media, and trends in weekly theme coverage.

Implementing a Multisite Clinical Trial in the Midst of an Ebola Outbreak: Lessons Learned From the Sierra Leone Trial to Introduce a Vaccine Against Ebola.

The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE), a phase 2/3 trial of investigational rVSV∆G-ZEBOV-GP vaccine, was conducted during an unprecedented Ebola epidemic. More than 8600 eligible healthcare and frontline response workers were individually randomized to immediate (within 7 days) or deferred (within 18-24 weeks) vaccination and followed for 6 months after vaccination for serious adverse events and Ebola virus infection. Key challenges included limited infrastructure to support trial activities, unreliable electricity, and staff with limited clinical trial experience. Study staff made substantial infrastructure investments, including renovation of enrollment sites, laboratories, and government cold chain facilities, and imported equipment to store and transport vaccine at ≤-60oC. STRIVE built capacity by providing didactic and practical research training to >350 staff, which was reinforced with daily review and feedback meetings. The operational challenges of safety follow-up were addressed by issuing mobile telephones to participants, making home visits, and establishing a nurse triage hotline. Before the Ebola outbreak, Sierra Leone had limited infrastructure and staff to conduct clinical trials. Without interfering with the outbreak response, STRIVE responded to an urgent need and helped build this capacity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

The Sierra Leone Trial to Introduce a Vaccine Against Ebola: An Evaluation of rVSV∆G-ZEBOV-GP Vaccine Tolerability and Safety During the West Africa Ebola Outbreak.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].