Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

Pneumonia in adults - Quality standard QS110

IntroductionThis quality standard covers adults (18 years and older) with a suspected or confirmed diagnosis of community acquired pneumonia. For more information see the pneumonia topic overview.Why this quality standard is neededPneumonia is an infection of the lung tissue. When a person has pneumonia the air sacs in their lungs become filled with microorganisms, fluid and inflammatory cells and their lungs are not able to work properly. Diagnosis of pneumonia is based on symptoms and signs of an acute lower respiratory tract infection, and can be confirmed by a chest X-ray showing new shadowing that is not due to any other cause (such as pulmonary oedema or infarction). The NICE guideline on pneumonia classifies pneumonia depending on the source of the infection as community acquired or hospital-acquired, which need different management strategies. Every year between 0.5% and 1% of adults in the UK will have community-acquired pneumonia. It is diagnosed in 5–12% of adults who present to GPs with symptoms of lower respiratory tract infection, and 22–42% of these are admitted to hospital, where the mortality rate is between 5% and 14%. Between 1.2% and 10% of adults admitted to hospital with community acquired pneumonia are managed in an intensive care unit, and for these patients the risk of dying is over 30%. More than half of pneumonia-related deaths occur in people older than 84 years.At any time, 1.5% of hospital patients in England have a hospital-acquired respiratory infection, more than half of which are hospital-acquired pneumonia and are not associated with intubation. Hospital-acquired pneumonia is estimated to increase a hospital stay by about 8 days and has a reported mortality rate ranging from 30–70%. There are variations in clinical management and outcomes across the UK

2019-nCoV (Wuhan virus), a novel Coronavirus: Human-to-human transmission, travel-related cases, and vaccine readiness

On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus

Experiences of Red River Métis Accessing COVID Vaccines: A partnership-based, whole-population linked administrative data study.

Objectives Red River Métis are Indigenous people hailing from the Canadian Prairies who have historically experienced poor health outcomes due to colonial practices. Researchers from the Manitoba Métis Federation (MMF) partnered with health services researchers to test whether MMF-led COVID initiatives were associated with access to COVID-19 testing and vaccines. Approach We linked the Métis Population Data-Base from the MMF (to identify Red River Métis) with whole-population COVID testing and vaccination data and health and social services administrative data (for information on sociodemographics and confounders) to complete this retrospective cohort study. We used restricted mean survival time models to test whether COVID-19 vaccination differed between Métis and all other Manitobans (AOM); models adjusted for demographics, comorbidities, and other characteristics (age, socioeconomic status, urbanicity, and mental health status). Data were stratified by sex and subsequent effect modification analyses tested whether associations differed by sex and physical health comorbidities. Results COVID testing rates were lower during the first year of the pandemic among Métis than among AOM. During the second year of the pandemic, this finding was reversed - Métis accessed tests at higher rates. There was no difference between Métis and AOM in accessing first vaccine doses before implementation of MMF-led initiatives. After initiatives were put in place, Métis received their second COVID vaccine, on average, 1.3 (95% CI 1.9-0.6) days sooner than AOM, after adjusting for confounders. Effect modification analyses showed this relationship was concentrated among females – female Métis received their second vaccine 1.7 (2.6-0.8) days sooner than female AOM; differences were non-significant for males. Métis with 2+ comorbidities received their vaccine second 2.9 (5.3-0.5) days sooner than AOM with 2+ comorbidities. Conclusion Public health initiatives prioritizing Métis for vaccines improved uptake. Initiatives led by Métis to improve COVID outcomes were critical to supporting Métis during the course of the pandemic. Public health response efforts need to operate from a standpoint that honours Indigenous sovereignty in their design and implementation

Artificial Nightlight Alters the Predator–Prey Dynamics of an Apex Carnivore

Artificial nightlight is increasingly recognized as an important environmental disturbance that influences the habitats and fitness of numerous species. However, its effects on wide‐ranging vertebrates and their interactions remain unclear. Light pollution has the potential to amplify land‐use change, and as such, answering the question of how this sensory stimulant affects behavior and habitat use of species valued for their ecological roles and economic impacts is critical for conservation and land‐use planning. Here, we combined satellite‐derived estimates of light pollution, with GPS‐data from cougars Puma concolor (n = 56), mule deer Odocoileus hemionus (n = 263) and locations of cougar‐killed deer (n = 1562 carcasses), to assess the effects of light exposure on mammal behavior and predator–prey relationships across wildland–urban gradients in the southwestern United States. Our results indicate that deer used the anthropogenic environments to access forage and were more active at night than their wildland conspecifics. Despite higher nightlight levels, cougars killed deer at the wildland–urban interface, but hunted them in the relatively darkest locations. Light had the greatest effect of all covariates on where cougars killed deer at the wildland–urban interface. Both species exhibited functional responses to light pollution at fine scales; individual cougars and deer with less light exposure increasingly avoided illuminated areas when exposed to greater radiance, whereas deer living in the wildland–urban interface selected elevated light levels. We conclude that integrating estimates of light pollution into ecological studies provides crucial insights into how the dynamic human footprint can alter animal behavior and ecosystem function across spatial scales

Enrichment and characterization of ammonia-oxidizing archaea from the open ocean : phylogeny, physiology and stable isotope fractionation

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in The ISME Journal 5 (2011): 1796–1808, doi:10.1038/ismej.2011.58.Archaeal genes for ammonia oxidation are widespread in the marine environment, but direct physiological evidence for ammonia oxidation by marine archaea is limited. We report the enrichment and characterization of three strains of pelagic ammonia-oxidizing archaea (AOA) from the north Pacific Ocean that have been maintained in laboratory culture for over three years. Phylogenetic analyses indicate the three strains belong to a previously identified clade of water column-associated AOA and possess 16S rRNA genes and ammonia monooxygenase subunit a (amoA) genes highly similar (98-99% identity) to those recovered in DNA and cDNA clone libraries from the open ocean. The strains grow in natural seawater-based liquid medium while stoichiometrically converting ammonium (NH4 +) to nitrite (NO2 -). Ammonia oxidation by the enrichments is only partially inhibited by allylthiourea at concentrations known to inhibit cultivated ammonia-oxidizing bacteria. The three strains were used to determine the nitrogen stable isotope effect (15εNH3) during archaeal ammonia oxidation, an important parameter for interpreting stable isotope ratios in the environment. Archaeal 15εNH3 ranged from 13- 41‰, within the range of that previously reported for ammonia-oxidizing bacteria. Despite low amino acid identity between the archaeal and bacterial Amo proteins, their functional diversity as captured by 15εNH3 is similar.This work was supported by a Woods Hole Oceanographic Institution (WHOI) Postdoctoral Scholar fellowship to AES and the WHOI Ocean Life Institute

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification