A Baker\u27s Dozen of Top Antimicrobial Stewardship Intervention Publications in 2017

With an increasing number of antimicrobial stewardship-related articles published each year, attempting to stay current is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related peer-reviewed literature that detailed an actionable intervention for 2017. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight the actionable intervention used by antimicrobial stewardship programs to provide key stewardship literature for training and teaching and identify potential intervention opportunities within their institutions

Cusp energetic particle events: Implications for a major acceleration region of the magnetosphere

The Charge and Mass Magnetospheric Ion Composition Experiment (CAMMICE) on board the Polar spacecraft observed 75 energetic particle events in 1996 while the satellite was at apogee. All of these events were associated with a decrease in the magnitude of the local magnetic field measured by the Magnetic Field Experiment (MFE) on Polar. These new events showed several unusual features: (1) They were detected in the dayside polar cusp near the apogee of Polar with about 79% of the total events in the afternoonside and 21% in the morningside; (2) an individual event could last for hours; (3) the measured helium ion had energies up to and many times in excess of 2.4 MeV; (4) the intensity of 1–200 KeV/e helium was anticorrelated with the magnitude of the local geomagnetic field but correlated with the turbulent magnetic energy density; (5) the events were associated with an enhancement of the low-frequency magnetic noise, the spectrum of which typically extends from a few hertz to a few hundreds of hertz as measured by the Plasma Wave Instrument (PWI) on Polar; and (6) a seasonal variation was found for the occurrence rate of the events with a maximum in September. These characterized a new phenomenon which we are calling cusp energetic particle (CEP) events. The observed high charge state of helium and oxygen ions in the CEP events indicates a solar source for these particles. Furthermore, the measured 0.52–1.15 MeV helium flux was proportional to the difference between the maximum and the minimum magnetic field in the event. A possible explanation is that the energetic helium ions are energized from lower energy helium by a local acceleration mechanism associated with the high-altitude dayside cusp. These observations represent a potential discovery of a major acceleration region of the magnetosphere

A Baker\u27s Dozen of Top Antimicrobial Stewardship Intervention Publications in 2017

With an increasing number of antimicrobial stewardship-related articles published each year, attempting to stay current is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related peer-reviewed literature that detailed an actionable intervention for 2017. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight the actionable intervention used by antimicrobial stewardship programs to provide key stewardship literature for training and teaching and identify potential intervention opportunities within their institutions

Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relaps

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

A multilab study of bilingual infants: Exploring the preference for infant-directed speech

From the earliest months of life, infants prefer listening to and learn better from infant-directed speech (IDS) compared with adult-directed speech (ADS). Yet IDS differs within communities, across languages, and across cultures, both in form and in prevalence. This large-scale, multisite study used the diversity of bilingual infant experiences to explore the impact of different types of linguistic experience on infants’ IDS preference. As part of the multilab ManyBabies 1 project, we compared preference for North American English (NAE) IDS in lab-matched samples of 333 bilingual and 384 monolingual infants tested in 17 labs in seven countries. The tested infants were in two age groups: 6 to 9 months and 12 to 15 months. We found that bilingual and monolingual infants both preferred IDS to ADS, and the two groups did not differ in terms of the overall magnitude of this preference. However, among bilingual infants who were acquiring NAE as a native language, greater exposure to NAE was associated with a stronger IDS preference. These findings extend the previous finding from ManyBabies 1 that monolinguals learning NAE as a native language showed a stronger IDS preference than infants unexposed to NAE. Together, our findings indicate that IDS preference likely makes similar contributions to monolingual and bilingual development, and that infants are exquisitely sensitive to the nature and frequency of different types of language input in their early environments

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer