The role of airway microbiome in corticosteroid response in asthma is unknown.
To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with ...patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.
16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.
Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.
A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
COVID-19 is primarily a respiratory illness, and smoking adversely impacts the respiratory and immune systems; this confluence may therefore incentivize smokers to quit. The present study, conducted ...in four high-income countries during the first global wave of COVID-19, examined the association between COVID-19 and: (1) thoughts about quitting smoking; (2) changes in smoking (quit attempt, reduced or increased smoking, or no change); and (3) factors related to a positive change (making a quit attempt or reducing smoking) based on an adapted framework of the Health Belief Model.
This cross-sectional study included 6870 adult smokers participating in the Wave 3 (2020) ITC Four Country Smoking and Vaping Survey conducted in Australia, Canada, England, and United States (US). These four countries had varying responses to the pandemic by governments and public health, ranging from advising voluntary social distancing to implementing national and subnational staged lockdowns. Considering these varying responses, and the differences in the number of confirmed cases and deaths (greatest in England and the US and lowest in Australia), smoking behaviours related to COVID-19 may have differed between countries. Other factors that may be related to changes in smoking because of COVID-19 were also explored (e.g., sociodemographics, nicotine dependence, perceptions about personal and general risks of smoking on COVID-19). Regression analyses were conducted on weighted data.
Overall, 46.7% of smokers reported thinking about quitting because of COVID-19, which differed by country (p<0.001): England highest (50.9%) and Australia lowest (37.6%). Thinking about quitting smoking because of COVID-19 was more frequent among: females, ethnic minorities, those with financial stress, current vapers, less dependent smokers (non-daily and fewer cigarettes smoked/day), those with greater concern about personal susceptibility of infection, and those who believe COVID-19 is more severe for smokers. Smoking behaviour changes due to COVID-19 were: 1.1% attempted to quit, 14.2% reduced smoking, and 14.6% increased smoking (70.2% reported no change). Positive behaviour change (tried to quit/reduced smoking) was reported by 15.5% of smokers, which differed by country (p = 0.02), where Australia had significantly lower rates than the other three countries. A positive behavioural smoking change was more likely among smokers with: lower dependence, greater concern about personal susceptibility to infection, and believing that COVID-19 is more severe for smokers.
Though nearly half of smokers reported thinking about quitting because of COVID-19, the vast majority did not change their smoking behaviour. Smokers were more likely to try and quit or reduce their smoking if they had greater concern about susceptibility and severity of COVID-19 related to smoking. Smokers in Australia were least likely to reduce or try to quit smoking, which could be related to the significantly lower impact of COVID-19 during the early phase of the pandemic relative to the other countries.
The DNA sequencing technologies in use today produce either highly accurate short reads or less-accurate long reads. We report the optimization of circular consensus sequencing (CCS) to improve the ...accuracy of single-molecule real-time (SMRT) sequencing (PacBio) and generate highly accurate (99.8%) long high-fidelity (HiFi) reads with an average length of 13.5 kilobases (kb). We applied our approach to sequence the well-characterized human HG002/NA24385 genome and obtained precision and recall rates of at least 99.91% for single-nucleotide variants (SNVs), 95.98% for insertions and deletions <50 bp (indels) and 95.99% for structural variants. Our CCS method matches or exceeds the ability of short-read sequencing to detect small variants and structural variants. We estimate that 2,434 discordances are correctable mistakes in the 'genome in a bottle' (GIAB) benchmark set. Nearly all (99.64%) variants can be phased into haplotypes, further improving variant detection. De novo genome assembly using CCS reads alone produced a contiguous and accurate genome with a contig N50 of >15 megabases (Mb) and concordance of 99.997%, substantially outperforming assembly with less-accurate long reads.
In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A ...phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.
In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the
,
,
, and
loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause.
In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval CI, 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
In the face of rapid environmental and cultural change, orthodox concepts in restoration ecology such as historical fidelity are being challenged. Here we re-examine the diverse roles played by ...historical knowledge in restoration, and argue that these roles remain vitally important. As such, historical knowledge will be critical in shaping restoration ecology in the future. Perhaps the most crucial role in shifting from the present version of restoration ecology ("v1.0") to a newer formulation ("v2.0") is the value of historical knowledge in guiding scientific interpretation, recognizing key ecological legacies, and influencing the choices available to practitioners of ecosystem intervention under conditions of open-ended and rapid change.
Hosts are likely to respond to parasitic infections by a combination of resistance (expulsion of pathogens) and tolerance (active mitigation of pathology). Of these strategies, the basis of tolerance ...in animal hosts is relatively poorly understood, with especially little known about how tolerance is manifested in natural populations. We monitored a natural population of field voles using longitudinal and cross-sectional sampling modes and taking measurements on body condition, infection, immune gene expression, and survival. Using analyses stratified by life history stage, we demonstrate a pattern of tolerance to macroparasites in mature compared to immature males. In comparison to immature males, mature males resisted infection less and instead increased investment in body condition in response to accumulating burdens, but at the expense of reduced reproductive effort. We identified expression of the transcription factor Gata3 (a mediator of Th2 immunity) as an immunological biomarker of this tolerance response. Time series data for individual animals suggested that macroparasite infections gave rise to increased expression of Gata3, which gave rise to improved body condition and enhanced survival as hosts aged. These findings provide a clear and unexpected insight into tolerance responses (and their life history sequelae) in a natural vertebrate population. The demonstration that such responses (potentially promoting parasite transmission) can move from resistance to tolerance through the course of an individual's lifetime emphasises the need to incorporate them into our understanding of the dynamics and risk of infection in the natural environment. Moreover, the identification of Gata3 as a marker of tolerance to macroparasites raises important new questions regarding the role of Th2 immunity and the mechanistic nature of the tolerance response itself. A more manipulative, experimental approach is likely to be valuable in elaborating this further.
An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are ...unknown.
The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh.
Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the 3H-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA.
In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the 3H-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p<0.05).
These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time.
BACKGROUND
Hospital‐acquired disability (HAD) is common and often related to low physical activity while in the hospital.
OBJECTIVE
To examine whether wearable hospital activity trackers can be used ...to predict HAD.
DESIGN
A prospective observational study between January 2016 and March 2017.
SETTING
An academic medical center.
PARTICIPANTS
Community‐dwelling older adults, aged 60 years or older, enrolled within 24 hours of admission to general medicine (n = 46).
MAIN MEASURES
Primary outcome was HAD, defined as having one or more new activity of daily living deficits, decline of four or greater on the Late‐Life Function and Disability Instrument (calculated between baseline and discharge), or discharge to a skilled nursing facility. Hospital activity (mean active time, mean sedentary time, and mean step counts per day) was measured using ankle‐mounted accelerometers. The association of the literature‐based threshold of 900 steps/day with HAD was also evaluated.
RESULTS
Mean age was 73.2 years (SD = 9.5 years), 48% were male, and 76% were white. Median length of stay was 4 days (interquartile range IQR = 2.0‐6.0 days); 61% (n = 28) reported being able to walk without assistance of another person or walking aid at baseline. Median daily activity time and step counts were 1.1 h/d (IQR = 0.7‐1.7 h/d) and 1455.7 steps/day (IQR = 908.5‐2643 steps/day), respectively. Those with HAD (41%; n = 19) had lower activity time (0.8 vs 1.4 h/d; P = .04) and fewer step counts (1186 vs 1808 steps/day; P = .04), but no difference in sedentary time, compared to those without HAD. The 900 steps/day threshold had poor sensitivity (40%) and high specificity (85%) for detecting HAD.
CONCLUSIONS
Low hospital physical activity, as measured by wearable accelerometers, is associated with HAD. Clinicians can utilize wearable technology data to refer patients to physical/occupational therapy services or other mobility interventions, like walking programs. J Am Geriatr Soc 68:261–265, 2020
Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic ...variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.
In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes GASP initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes U-BIOPRED project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.
We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio OR 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).
We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.
Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
Standard economic theory predicts that exploitation alone is unlikely to result in species extinction because of the escalating costs of finding the last individuals of a declining species. We argue ...that the human predisposition to place exaggerated value on rarity fuels disproportionate exploitation of rare species, rendering them even rarer and thus more desirable, ultimately leading them into an extinction vortex. Here we present a simple mathematical model and various empirical examples to show how the value attributed to rarity in some human activities could precipitate the extinction of rare species-a concept that we term the anthropogenic Allee effect. The alarming finding that human perception of rarity can precipitate species extinction has serious implications for the conservation of species that are rare or that may become so, be they charismatic and emblematic or simply likely to become fashionable for certain activities.
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