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Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized COVID-19 patients. Integrated analysis using k-means reveal four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors are delineated by high and low antibody responses. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the “Interferon paradox” previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.

With the entire Small Magellanic Cloud (SMC) mapped by the Spitzer Space Telescope and Herschel Space Observatory, we were able to search 8-250 micron images in order to identify infrared (IR) emission associated with SMC supernova remnants (SNRs). A valid detection had to correspond with known X-ray, Halpha and radio emission from the SNRs. From the 24 known SNRs, we made 5 positive detections with another 5 possible detections. Two detections are associated with pulsars or pulsar wind nebula, and another three detections are part of the extended nebulous emission from the SNRs. We modelled dust emission where fast moving electrons are predicted to collide and heat dust grains which then radiate in IR. With known distance (62.44+-0.47kpc), measured SNR sizes, electron densities, temperatures from X-ray emission as well as hydrogen densities, the modelling of SMC SNRs is straightforward. If the higher range of hydrogen and electron densities were to be accepted, we would expect almost all SMC SNRs to be detected in the IR, at least at 24 micron, but the actual detection rate is only 25%. One possible and common explanation for this discrepancy is that small grains have been destroyed by the SNRs shockwave. However, within the uncertainties of hydrogen and electron densities, we find that infrared dust emission can be explained reasonably well, without invoking dust destruction. There is no conclusive evidence that SNRs destroy swept-up ISM dust., Comment: accepted for publication in MNRAS; 33 pages

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen. However, it is currently not clear what drives receptor selectivity. Here, we use five representative SLBRs and identify regions of the receptor binding site that are hypervariable in sequence and structure. We show that these regions control the identity of the preferred carbohydrate ligand using chimeragenesis and single amino acid substitutions. We further evaluate how the identity of the preferred ligand affects the interaction with glycoprotein receptors in human saliva and plasma samples. As point mutations can change the preferred human receptor, these studies suggest how streptococci may adapt to changes in the environmental glycan repertoire.

Wildfire dynamics are changing around the world and understanding their effects on ecological communities and landscapes is urgent and important. We report detailed food webs for unburned, low-to-moderate and high severity burned habitats three years post-fire in the Eldorado National Forest, California. The cumulative cross-habitat food web contains 3,084 ontogenetic stages (nodes) or plant parts comprising 849 species (including 107 primary producers, 634 invertebrates, 94 vertebrates). There were 178,655 trophic interactions between these nodes. We provide information on taxonomy, body size, biomass density and trophic interactions under each of the three burn conditions. We detail 19 sampling methods deployed across 27 sites (nine in each burn condition) used to estimate the richness, body size, abundance and biomass density estimates in the node lists. We provide the R code and raw data to estimate summarized node densities and assign trophic links.

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen. However, it is currently not clear what drives receptor selectivity. Here, we use five representative SLBRs and identify regions of the receptor binding site that are hypervariable in sequence and structure. We show that these regions control the identity of the preferred carbohydrate ligand using chimeragenesis and single amino acid substitutions. We further evaluate how the identity of the preferred ligand affects the interaction with glycoprotein receptors in human saliva and plasma samples. As point mutations can change the preferred human receptor, these studies suggest how streptococci may adapt to changes in the environmental glycan repertoire.

Kathryn M Luly,1,2 Huilin Yang,2,3 Stephen J Lee,2,3 Wentao Wang,1,2 Seth D Ludwig,2,3 Haley E Tarbox,4 David R Wilson,1,2,5 Jordan J Green,1– 3,5– 10 Jamie B Spangler1– 3,6,8 1Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; 4Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA; 5Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA; 6Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 7Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 8Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 9Departments of Neurosurgery and Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 10Department of Materials Science & Engineering, Johns Hopkins University, Baltimore, MD, USACorrespondence: Jamie B Spangler, Departments of Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University, 400 N Broadway, Smith 5011, Baltimore, MD, 21231, USA, Tel +1 443 287-1708, Email jamie.spangler@jhu.edu Jordan J Green, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 400 N Broadway, Smith 5017, Baltimore, MD, 21231, USA, Tel +1 410 614-9113, Email green@jhu.eduPurpose: Transient transfection is an essential tool for recombinant protein production, as it allows rapid screening for expression without stable integration of genetic material into a target cell genome. Poly(ethylenimine) (PEI) is the current gold standard for transient gene transfer, but transfection efficiency and the resulting protein yield are limited by the polymer’s to

With the entire Small Magellanic Cloud (SMC) mapped by the Spitzer Space Telescope and Herschel Space Observatory, we were able to search 8-250 micron images in order to identify infrared (IR) emission associated with SMC supernova remnants (SNRs). A valid detection had to correspond with known X-ray, Halpha and radio emission from the SNRs. From the 24 known SNRs, we made 5 positive detections with another 5 possible detections. Two detections are associated with pulsars or pulsar wind nebula, and another three detections are part of the extended nebulous emission from the SNRs. We modelled dust emission where fast moving electrons are predicted to collide and heat dust grains which then radiate in IR. With known distance (62.44+-0.47kpc), measured SNR sizes, electron densities, temperatures from X-ray emission as well as hydrogen densities, the modelling of SMC SNRs is straightforward. If the higher range of hydrogen and electron densities were to be accepted, we would expect almost all SMC SNRs to be detected in the IR, at least at 24 micron, but the actual detection rate is only 25%. One possible and common explanation for this discrepancy is that small grains have been destroyed by the SNRs shockwave. However, within the uncertainties of hydrogen and electron densities, we find that infrared dust emission can be explained reasonably well, without invoking dust destruction. There is no conclusive evidence that SNRs destroy swept-up ISM dust., Comment: accepted for publication in MNRAS; 33 pages

First published online: 15 September 2021, The assessment of schizotypy and schizophrenia-spectrum psychopathology has historically been adversely impacted by multiple forms of measurement bias, including racial bias. The Multidimensional Schizotypy Scale (MSS) was developed using modern scale construction methods to minimize measurement bias in the assessment of schizotypic traits. However, studies have not examined the validity of the measurement across different racial groups. The present study examined whether the associations of MSS positive, negative, and disorganized schizotypy subscales with interview-assessed ratings of functioning, schizophrenia-spectrum personality traits, and depressive disorders were generally comparable across nonclinically ascertained samples of Black (n = 46), Asian (n = 87), and White (n = 116) young adults. Consistent with previous findings, all three schizotypy subscales were associated with impairment and schizotypal and paranoid traits. Negative schizotypy was associated with schizoid traits, and disorganized schizotypy was associated with depressive disorders. These associations were comparable across the racial groups, supporting the use of the MSS in these groups. Culturally and empirically valid assessments are essential for providing accurate assessments across racial/ethnic groups and reducing the risk of overpathologizing people of color. The present findings support the cross-cultural validity of the MSS; however, future studies should expand upon these findings by including more diverse samples and longitudinal designs.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure.

It is commonly assumed that asexual lineages are short-lived evolutionarily, yet many asexual organisms can generate genetic and phenotypic variation, providing an avenue for further evolution. Previous work on the asexual plant pathogen Phytophthora ramorum NA1 revealed considerable genetic variation in the form of Structural Variants (SVs). To better understand how SVs arise and their significance to the California NA1 population, we studied the evolutionary histories of SVs and the forest conditions associated with their emergence. Ancestral state reconstruction suggests that SVs arose by somatic mutations among multiple independent lineages, rather than by recombination. We asked if this unusual phenomenon of parallel evolution between isolated populations is transmitted to extant lineages and found that SVs persist longer in a population if their genetic background had a lower mutation load. Genetic parallelism was also found in geographically distant demes where forest conditions such as host density, solar radiation, and temperature, were similar. Parallel SVs overlap with genes involved in pathogenicity such as RXLRs and have the potential to change the course of an epidemic. By combining genomics and environmental data, we identified an unexpected pattern of repeated evolution in an asexual population and identified environmental factors potentially driving this phenomenon.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure.

ImportanceOne major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.ObservationsNational Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presen

It is commonly assumed that asexual lineages are short-lived evolutionarily, yet many asexual organisms can generate genetic and phenotypic variation, providing an avenue for further evolution. Previous work on the asexual plant pathogen Phytophthora ramorum NA1 revealed considerable genetic variation in the form of Structural Variants (SVs). To better understand how SVs arise and their significance to the California NA1 population, we studied the evolutionary histories of SVs and the forest conditions associated with their emergence. Ancestral state reconstruction suggests that SVs arose by somatic mutations among multiple independent lineages, rather than by recombination. We asked if this unusual phenomenon of parallel evolution between isolated populations is transmitted to extant lineages and found that SVs persist longer in a population if their genetic background had a lower mutation load. Genetic parallelism was also found in geographically distant demes where forest conditions such as host density, solar radiation, and temperature, were similar. Parallel SVs overlap with genes involved in pathogenicity such as RXLRs and have the potential to change the course of an epidemic. By combining genomics and environmental data, we identified an unexpected pattern of repeated evolution in an asexual population and identified environmental factors potentially driving this phenomenon.

© The Author(s) 2020. To land a job as an art director, the presentation of a strong conceptualized portfolio is only part of the equation. What additional knowledge helps the novice creative not only during the initial interview but to succeed once they land the job? This study looked to identify what additional skills and traits working art and creative directors felt young creatives needed beyond their portfolio in order to land their first job in advertising. The results suggest ways forward in how to prepare students to incorporate design, business, and personal skills into a well-rounded creative and personal brand.

© The Author(s) 2020. To land a job as an art director, the presentation of a strong conceptualized portfolio is only part of the equation. What additional knowledge helps the novice creative not only during the initial interview but to succeed once they land the job? This study looked to identify what additional skills and traits working art and creative directors felt young creatives needed beyond their portfolio in order to land their first job in advertising. The results suggest ways forward in how to prepare students to incorporate design, business, and personal skills into a well-rounded creative and personal brand.

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure.

The relationship between account management and creative is a complicated and ever-changing one. A common theme in the advertising literature is that account and creative teams sometimes struggle with intra-agency communication. This article looks at why communication is still an issue today and what knowledge modern account and creative teams need to know about the others’ role in the agency to close the long-standing communication gap. We asked both account managers and art and creative directors (creatives) what they wished the other understood about their roles within the agency. From their answers, we identify pedagogical suggestions for advertising professors as they work to better prepare students for careers in the industry.

The relationship between account management and creative is a complicated and ever-changing one. A common theme in the advertising literature is that account and creative teams sometimes struggle with intra-agency communication. This article looks at why communication is still an issue today and what knowledge modern account and creative teams need to know about the others’ role in the agency to close the long-standing communication gap. We asked both account managers and art and creative directors (creatives) what they wished the other understood about their roles within the agency. From their answers, we identify pedagogical suggestions for advertising professors as they work to better prepare students for careers in the industry.

IMPORTANCE: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. OBSERVATIONS: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral p

ObjectiveTo compare nurse preparedness and quality of patient handoff during interfacility transfers from a pretransfer emergency department to a PICU when conducted over telemedicine versus telephone.DesignCross-sectional nurse survey linked with patient electronic medical record data using multivariable, multilevel analysis.SettingTertiary PICU within an academic children's hospital.ParticipantsPICU nurses who received a patient handoff between October 2017 and July 2018.InterventionsNone.Main results and measurementsAmong 239 eligible transfers, 106 surveys were completed by 55 nurses (44% survey response rate). Telemedicine was used for 30 handoffs (28%), and telephone was used for 76 handoffs (72%). Patients were comparable with respect to age, sex, race, primary spoken language, and insurance, but handoffs conducted over telemedicine involved patients with higher illness severity as measured by the Pediatric Risk of Mortality III score (4.4 vs 1.9; p = 0.05). After adjusting for Pediatric Risk of Mortality III score, survey recall time, and residual clustering by nurse, receiving nurses reported higher preparedness (measured on a five-point adjectival scale) following telemedicine handoffs compared with telephone handoffs (3.4 vs 3.1; p = 0.02). There were no statistically significant differences in both bivariable and multivariable analyses of handoff quality as measured by the Handoff Clinical Evaluation Exercise. Handoffs using telemedicine were associated with increased number of Illness severity, Patient summary, Action list, Situation awareness and contingency planning, Synthesis by receiver components (3.3 vs 2.8; p = 0.04), but this difference was not significant in the adjusted analysis (3.1 vs 2.9; p = 0.55).ConclusionsTelemedicine is feasible for nurse-to-nurse handoffs of critically ill patients between pretransfer and receiving facilities and may be associated with increased perceived and objective nurse preparedness upon patient arrival. Addition

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Although trisomy 12 (+12) chronic lymphocytic leukemia (CLL) comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphological and immunophenotypic features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 CLL have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter transformation, and other secondary cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 CLL, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identify protein-coding genes whose expression contributes to the unique pathophysiology of +12 CLL. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naive patients. We compared cases with +12 as the only cytogenetic abnormality to cases with only del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that CLL cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathway and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets.

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is critical for DA neurotransmission and homeostasis. DAT surface availability is regulated acutely by endocytic trafficking, and considerable effort has been directed toward understanding mechanisms that govern DAT's plasma membrane expression and postendocytic fate. Multiple studies have demonstrated DAT endocytic recycling and enhanced surface delivery in response to various stimuli. Paradoxically, imaging studies have not detected DAT targeting to classic recycling endosomes, suggesting that internalized DAT targets to either degradation or an undefined recycling compartment. Here, we leveraged PRIME (PRobe Incorporation Mediated by Enzyme) labeling to couple surface DAT directly to fluorophore, and tracked DAT's postendocytic itinerary in immortalized mesencephalic cells. Following internalization, DAT robustly targeted to retromer-positive endosomes, and DAT/retromer colocalization was observed in male mouse dopaminergic somatodendritic and terminal regions. Short hairpin RNA-mediated Vps35 knockdown revealed that DAT endocytic recycling requires intact retromer. DAT also targeted rab7-positive endosomes with slow, linear kinetics that were unaffected by either accelerating DAT internalization or binding a high-affinity cocaine analog. However, cocaine increased DAT exit from retromer-positive endosomes significantly. Finally, we found that the DAT carboxy-terminal PDZ-binding motif was required for DAT recycling and exit from retromer. These results define the DAT recycling mechanism and provide a unifying explanation for previous, seemingly disparate, DAT endocytic trafficking findings.

Although trisomy 12 (+12) chronic lymphocytic leukemia (CLL) comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphological and immunophenotypic features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 CLL have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter transformation, and other secondary cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 CLL, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identify protein-coding genes whose expression contributes to the unique pathophysiology of +12 CLL. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naive patients. We compared cases with +12 as the only cytogenetic abnormality to cases with only del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that CLL cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathway and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets.

Background and purposeThe advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial.MethodsThe study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria.ResultsDerived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment.ConclusionsIt is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

BackgroundThe IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial.MethodsWe used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration.FindingsOf 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]).InterpretationDelays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials.FundingUS National Institutes of Health and National Institute of Neurological Disorders and Stroke.

Published in Engineer, p55-59, January-April 2009.

This thesis is a history of the legions and auxiliary units of the Roman province of Moesia from 29 BC to AD 235. Some of the principal battles and campaigns undertaken in the area are discussed; however, the focus of the study is the movement of those units both in and out of the province, and also their emplacement, where possible, in the numerous forts so far found in Moesia. A variety of different types of evidence are used: inscriptions, and in particular stone inscriptions and the bronze diplomas are the most valuable sources; the ancient authors are important, and Tacitus, Josephus, Cassius Dio, and Ptolemy are the most valuable, although others are used. There are a handful of conclusions drawn from this study. Generally, during the Julio-Claudian period military units tended to cluster around each other. In the second and third centuries, they are more spread out, and tend to be fairly evenly distributed along the Danube. During the two major campaigns that happened over the course of the years from 29 BC to AD 235, there was a significant influx of troops, and in particular auxiliary units, which were well suited to the conditions. The total legionary disposition remained fairly consistent from Vespasian to Severus Alexander. In the second century, units became stationary and vexillations were often dispatched when the gravity of the moment called for reinforcements., Master of Arts (MA)

Despite the large corpus of scholarly writing about the Roman army, the military oath, or sacramentum, of the late Republican legions has not been studied at length. Since the fall of the Republican was rooted in the struggle for political and military dominance by individuals, the loyalty of the legions to these commanders is of utmost importance. The first chapter focuses on the geographic and social origins of the soldiers of the late Republic, which have been studied extensively and provide a background from which to assess the composition of the army. As well, the conditions of service for this period are significant factors affecting the obedience of soldiers to their commanders, and the second chapter of this thesis places particular emphasis on problems of length of service, pay, booty and plunder, and military discipline. This framework of conditions and characteristics supports the analysis of the sacramentum itself in the third chapter. The textual evidence for the oath, both direct and indirect, are gathered for comparative purposes and applied to historical anecdotes of loyal and disloyal behaviour for the period in question. Conclusions about the religion and psychological impact of the sacramentum complete this assessment of the effectiveness of the Roman military oath in the late Republic., Master of Arts (MA)

Over time, underground warfare continues to maintain its allure in conflict as combatants seek a competitive edge over their opponent. Currently, most US doctrine addressing the subterranean environment is from a tactical perspective, focusing on technology, techniques, and procedures to combat a subterranean threat. Understanding subterranean operations remains critical as the United States endeavors to understand themselves, its enemies, and the future environment while preserving the American way of life. Through historical analysis and the development of a subterranean typology, this study provides the operational planner with a better understanding of the operational implications of a subterranean fight. This understanding is critical to the success of the United States in large scale combat operations. It will allow the operational level planner to better understand the operating environment, estimate the enemy's capabilities, and provide the combatant commander with more suitable options for success. The subterranean threat is not an army problem, rather a defense problem requiring combined resources and assets at all echelons. However, physical effects are only cogent when they are followed by deliberate cognitive design and virtual shaping effects. At the operational level, the United States must reshape their mental model and reframe the problem in order to shape the deep fight against an enemy whose subterranean networks make them impervious to our traditional, lethal, deep-fires effects. While still an important facet, the answer to the subterranean threat is not in the next technological advancement or tactical solution, rather it is in the operational artist's creative and critical thinking and ability to reframe the problem, apply systematic thinking, and provide better solutions to the commander.

Map of the Midland Terminal Railway system in the Pikes Peak area. Shows route of the Midland, including location of tunnels, as well as other railroads: the Atchison, Topeka dn Santa Fe; the Denver and Rio Grande; the Pikes Peak Cog Road; the Colorado Midland Railway; and the Colorado Springs & Cripple Creek District Railway. Identifies some mines and mills, parks, canyons, mountains and creeks. Detail shows Midland Terminal roundhouse and yards., Logo says: Cripple Creek Scenic Line, Ute Indian Trail Route