Diverse tsunamigenesis triggered by the Hunga Tonga-Hunga Ha'apai eruption.

On the evening of 15 January 2022, the Hunga Tonga-Hunga Ha'apai volcano1 unleashed a violent underwater eruption, blanketing the surrounding land masses in ash and debris2,3. The eruption generated tsunamis observed around the world. An event of this type last occurred in 1883 during the eruption of Krakatau4, and thus we have the first observations of a tsunami from a large emergent volcanic eruption captured with modern instrumentation. Here we show that the explosive eruption generated waves through multiple mechanisms, including: (1) air-sea coupling with the initial and powerful shock wave radiating out from the explosion in the immediate vicinity of the eruption; (2) collapse of the water cavity created by the underwater explosion; and (3) air-sea coupling with the air-pressure pulse that circled the Earth several times, leading to a global tsunami. In the near field, tsunami impacts are strongly controlled by the water-cavity source whereas the far-field tsunami, which was unusually persistent, can be largely described by the air-pressure pulse mechanism. Catastrophic damage in some harbours in the far field was averted by just tens of centimetres, implying that a modest sea level rise combined with a future, similar event would lead to a step-function increase in impacts on infrastructure. Piecing together the complexity of this event has broad implications for coastal hazards in similar geophysical settings, suggesting a currently neglected source of global tsunamis.

RSV-related Community COPD Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study.

RATIONALE: Respiratory syncytial virus (RSV) is a common global respiratory virus increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults with acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. OBJECTIVES: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. METHODS: Participants were recruited at specialist clinics in London, UK and Groningen, NL from 2017 and observed for three consecutive RSV seasons, during exacerbations and at least twice yearly. RSV infections were detected by reverse transcription-polymerase chain reaction (RT-PCR) and serologic testing. MEASUREMENTS AND MAIN RESULTS: 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8·7% of total); of these, seven were detected only on PCR, 16 only on serology and 4 by both methods. Increases in RSV specific N-protein antibody were as sensitive as antibody to pre-F or post-F for serodiagnosis of RSV related exacerbations. CONCLUSIONS: RSV is associated with 8.7% of outpatient managed COPD exacerbations in this study. Antibodies to RSV-N protein may have diagnostic value, potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Selected updates on chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is preventable disease and yet it remains the third greatest cause of death worldwide. This review focuses on recent updates in COPD research which have had an impact on our understanding of the epidemiology and pathophysiology of COPD. RECENT FINDINGS: Epidemiological studies of COPD have moved towards trying to understand the global impact of COPD particularly in low- and middle-income countries where disease prevalence continues to increase. In addition, we are beginning to uncover the impact of air pollution on COPD development with recent work showing a relationship between air pollution and COPD exacerbations. Advances in understanding early origins and early development of COPD have the potential to intervene earlier in the disease course to prevent disease progression. Although biomarkers such as peripheral blood eosinophilia have led to trials of biologic agents in COPD suggesting we may be entering an exciting new biologic era in COPD. SUMMARY: Recent advances suggest there may be a relationship between air pollution and COPD exacerbations. This requires further research to influence environmental policy. New clinical trials of biologics targeting TH2 inflammation in COPD suggest that targeted treatments with biologics may be a possibility COPD.

Diversification Rate is Associated with Rate of Molecular Evolution in Ray-Finned Fish (Actinopterygii).

Understanding the factors that drive diversification of taxa across the tree of life is a key focus of macroevolutionary research. While the effects of life history, ecology, climate and geography on diversity have been studied for many taxa, the relationship between molecular evolution and diversification has received less attention. However, correlations between rates of molecular evolution and diversification rate have been detected in a range of taxa, including reptiles, plants and birds. A correlation between rates of molecular evolution and diversification rate is a prediction of several evolutionary theories, including the evolutionary speed hypothesis which links variation in mutation rates to differences in speciation rates. If it is widespread, such correlations could also have significant practical impacts, if they are not adequately accounted for in phylogenetic inference of evolutionary rates and timescales. Ray-finned fish (Actinopterygii) offer a prime target to test for this relationship due to their extreme variation in clade size suggesting a wide range of diversification rates. We employ both a sister-pairs approach and a whole-tree approach to test for correlations between substitution rate and net diversification. We also collect life history and ecological trait data and account for potential confounding factors including body size, latitude, max depth and reef association. We find evidence to support a relationship between diversification and synonymous rates of nuclear evolution across two published backbone phylogenies, as well as weak evidence for a relationship between mitochondrial nonsynonymous rates and diversification at the genus level.

Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection.

Rationale: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology. Objectives: To determine whether volatile organic compound measurement could distinguish viral from bacterial infection in COPD. Methods: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas chromatography-mass spectrometry techniques were used to measure VOC production from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects experimentally challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compounds that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects experimentally challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compounds correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Conclusions: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.

Targeted Retreatment of Incompletely Recovered Chronic Obstructive Pulmonary Disease Exacerbations with Ciprofloxacin. A Double-Blind, Randomized, Placebo-controlled, Multicenter, Phase III Clinical Trial.

Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations are prone to nonrecovery, but there are no data about the effectiveness of retreatment for these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event.Objectives: To assess whether incompletely recovered COPD exacerbations benefit from additional treatment with ciprofloxacin, at Day 14.Methods: In a multicenter, randomized double-blind placebo-controlled trial, we studied retreatment with oral ciprofloxacin 500 mg or matched placebo twice daily for 7 days in patients with Global Initiative for Chronic Obstructive Lung Disease stage II-IV COPD and persistent symptoms and/or serum C-reactive protein ≥8 mg/L initiated 14 (±3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period.Measurements and Main Results: Among 826 patients screened at four centers, 144 eligible participants with incomplete recovery were randomized to receive ciprofloxacin (n = 72) or placebo (n = 72). Within 90 days of randomization, 57% of the patients in the ciprofloxacin group and 53% in the placebo group experienced one or more exacerbations. The median time to the next exacerbation was 32.5 days (interquartile range 13-50) in the placebo arm and 34 days (interquartile range 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio, 1.07; 95% confidence interval, 0.68-1.68; P = 0.76). No significant differences were seen in quality-of-life scores or lung function between the treatment groups.Conclusions: In patients with persistent symptoms and/or raised C-reactive protein 14 days after a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared with placebo. This suggests that nonrecovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with antiinflammatory therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02300220).

The Impact of the Tree Prior on Molecular Dating of Data Sets Containing a Mixture of Inter- and Intraspecies Sampling.

In Bayesian phylogenetic analyses of genetic data, prior probability distributions need to be specified for the model parameters, including the tree. When Bayesian methods are used for molecular dating, available tree priors include those designed for species-level data, such as the pure-birth and birth-death priors, and coalescent-based priors designed for population-level data. However, molecular dating methods are frequently applied to data sets that include multiple individuals across multiple species. Such data sets violate the assumptions of both the speciation and coalescent-based tree priors, making it unclear which should be chosen and whether this choice can affect the estimation of node times. To investigate this problem, we used a simulation approach to produce data sets with different proportions of within- and between-species sampling under the multispecies coalescent model. These data sets were then analyzed under pure-birth, birth-death, constant-size coalescent, and skyline coalescent tree priors. We also explored the ability of Bayesian model testing to select the best-performing priors. We confirmed the applicability of our results to empirical data sets from cetaceans, phocids, and coregonid whitefish. Estimates of node times were generally robust to the choice of tree prior, but some combinations of tree priors and sampling schemes led to large differences in the age estimates. In particular, the pure-birth tree prior frequently led to inaccurate estimates for data sets containing a mixture of inter- and intraspecific sampling, whereas the birth-death and skyline coalescent priors produced stable results across all scenarios. Model testing provided an adequate means of rejecting inappropriate tree priors. Our results suggest that tree priors do not strongly affect Bayesian molecular dating results in most cases, even when severely misspecified. However, the choice of tree prior can be significant for the accuracy of dating results in the case of data sets with mixed inter- and intraspecies sampling. [Bayesian phylogenetic methods; model testing; molecular dating; node time; tree prior.].

Role of microbiome in the pathophysiology and disease course of asthma.

PURPOSE OF REVIEW: The emergence of next-generation 16S rRNA sequencing techniques has facilitated a more detailed study of the body's microbiota and led to renewed interest in the association between microbial exposure and asthma inception. In this review, we evaluate the evidence that the respiratory tract and intestinal microbiota contribute to asthma pathogenesis and progression. RECENT FINDINGS: Human studies have revealed associations between the presence of potentially pathogenic bacteria in the respiratory tract in early life and subsequent risk of allergic sensitization and asthma. Similarly, alterations in the intestinal microbiota of neonates have also been shown to precede the development of asthma. Emerging evidence suggests that the lung microbiota is dysregulated in asthma with specific changes in bacterial diversity and community composition according to severity and phenotype. Studies using germ-free mice have been invaluable in moving our understanding from correlation to causation by demonstrating a mechanistic link between the neonatal microbiota and the development of allergic airway inflammation. SUMMARY: An expanding body of literature supports the hypothesis that early life microbial exposures and bacterial communities within the lung and/or intestine play an important role in shaping early immunological development. Perturbations in the microbiota may promote immune defects associated with the development of asthma and allergic sensitization.

Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK.

BACKGROUND: We describe drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) in a large tuberculosis (TB) centre in London; we identify the proportion who had risk factors for DILI and the timing and outcome of DILI. METHODS: We identified consecutive patients who developed DILI whilst on treatment for active TB; patients with active TB without DILI were selected as controls. Comprehensive demographic and clinical data, management and outcome were recorded. RESULTS: There were 105 (6.9%) cases of ATT-associated DILI amongst 1529 patients diagnosed with active TB between April 2010 and May 2014. Risk factors for DILI were: low patient weight, HIV-1 co-infection, higher baseline ALP, and alcohol intake. Only 25.7% of patients had British or American Thoracic Society defined criteria for liver test (LT) monitoring. Half (53%) of the cases occurred within 2 weeks of starting ATT and 87.6% occurred within 8 weeks. Five (4.8%) of seven deaths were attributable to DILI. CONCLUSIONS: Only a quarter of patients who developed DILI had British or American Thoracic Society defined criteria for pre-emptive LT monitoring, suggesting that all patients on ATT should be considered for universal liver monitoring particularly during the first 8 weeks of treatment.

Vibrational solvatochromism of nitrile infrared probes: beyond the vibrational Stark dipole approach.

Systematic probing of local environments around biopolymers is important for understanding their functions. Therefore, there has been growing interest in in situ measurements of molecular granularity and heterogeneity through the systematic analysis of vibrational frequency shifts of carbonyl and nitrile infrared probes by vibrational Stark dipole theory. However, here we show that the nitrile vibrational frequency shift induced by its interaction with the surrounding molecules cannot be solely described by electric field-based theory because of the exchange-repulsion and dispersion interaction contributions. Considering a variety of molecular environments ranging from bulk solutions to protein environments, we explore the distinct scenarios of solute-environment contacts and their traces in vibrational frequency shifts. We believe that the present work could provide a set of clues that could be potentially used to design a rigorous theoretical model linking vibrational solvatochromism and molecular topology in complex heterogeneous environments.

Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial.

BACKGROUND: Malignant pleural mesothelioma incidence continues to rise, with few available evidence-based therapeutic options. Results of previous non-randomised studies suggested that video-assisted thoracoscopic partial pleurectomy (VAT-PP) might improve symptom control and survival. We aimed to compare efficacy in terms of overall survival, and cost, of VAT-PP and talc pleurodesis in patients with malignant pleural mesothelioma. METHODS: We undertook an open-label, parallel-group, randomised, controlled trial in patients aged 18 years or older with any subtype of confirmed or suspected mesothelioma with pleural effusion, recruited from 12 hospitals in the UK. Eligible patients were randomly assigned (1:1) to either VAT-PP or talc pleurodesis by computer-generated random numbers, stratified by European Organisation for Research and Treatment of Cancer risk category (high vs low). The primary outcome was overall survival at 1 year, analysed by intention to treat (all patients randomly assigned to a treatment group with a final diagnosis of mesothelioma). This trial is registered with ClinicalTrials.gov, number NCT00821860. FINDINGS: Between Oct 24, 2003, and Jan 24, 2012, we randomly assigned 196 patients, of whom 175 (88 assigned to talc pleurodesis, 87 assigned to VAT-PP) had confirmed mesothelioma. Overall survival at 1 year was 52% (95% CI 41-62) in the VAT-PP group and 57% (46-66) in the talc pleurodesis group (hazard ratio 1·04 [95% CI 0·76-1·42]; p=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus ten (14%) of 73 patients who completed talc pleurodesis (p=0·019), as were respiratory complications (19 [24%] vs 11 [15%]; p=0·22) and air-leak beyond 10 days (five [6%] vs one [1%]; p=0·21), although not significantly so. Median hospital stay was longer at 7 days (IQR 5-11) in patients who received VAT-PP compared with 3 days (2-5) for those who received talc pleurodesis (p<0·0001). INTERPRETATION: VAT-PP is not recommended to improve overall survival in patients with pleural effusion due to malignant pleural mesothelioma, and talc pleurodesis might be preferable considering the fewer complications and shorter hospital stay associated with this treatment. FUNDING: BUPA Foundation.

Biogeographic calibrations for the molecular clock.

Molecular estimates of evolutionary timescales have an important role in a range of biological studies. Such estimates can be made using methods based on molecular clocks, including models that are able to account for rate variation across lineages. All clock models share a dependence on calibrations, which enable estimates to be given in absolute time units. There are many available methods for incorporating fossil calibrations, but geological and climatic data can also provide useful calibrations for molecular clocks. However, a number of strong assumptions need to be made when using these biogeographic calibrations, leading to wide variation in their reliability and precision. In this review, we describe the nature of biogeographic calibrations and the assumptions that they involve. We present an overview of the different geological and climatic events that can provide informative calibrations, and explain how such temporal information can be incorporated into dating analyses.