Relativistic cosmological perturbation scheme on a general background: scalar perturbations for irrotational dust

In standard perturbation approaches and N-body simulations, inhomogeneities are described to evolve on a predefined background cosmology, commonly taken as the homogeneous-isotropic solutions of Einstein's field equations (Friedmann-Lema\^itre-Robertson-Walker (FLRW) cosmologies). In order to make physical sense, this background cosmology must provide a reasonable description of the effective, i.e. spatially averaged, evolution of structure inhomogeneities also in the nonlinear regime. Guided by the insights that (i) the average over an inhomogeneous distribution of matter and geometry is in general not given by a homogeneous solution of general relativity, and that (ii) the class of FLRW cosmologies is not only locally but also globally gravitationally unstable in relevant cases, we here develop a perturbation approach that describes the evolution of inhomogeneities on a general background being defined by the spatially averaged evolution equations. This physical background interacts with the formation of structures. We derive and discuss the resulting perturbation scheme for the matter model `irrotational dust' in the Lagrangian picture, restricting our attention to scalar perturbations.Comment: 18 pages. Matches published version in CQ

New Exact Solutions of a Generalized Shallow Water Wave Equation

In this work an extended elliptic function method is proposed and applied to the generalized shallow water wave equation. We systematically investigate to classify new exact travelling wave solutions expressible in terms of quasi-periodic elliptic integral function and doubly-periodic Jacobian elliptic functions. The derived new solutions include rational, periodic, singular and solitary wave solutions. An interesting comparison with the canonical procedure is provided. In some cases the obtained elliptic solution has singularity at certain region in the whole space. For such solutions we have computed the effective region where the obtained solution is free from such a singularity.Comment: A discussion about singularity and some references are added. To appear in Physica Script

Observational constraints on inhomogeneous cosmological models without dark energy

It has been proposed that the observed dark energy can be explained away by the effect of large-scale nonlinear inhomogeneities. In the present paper we discuss how observations constrain cosmological models featuring large voids. We start by considering Copernican models, in which the observer is not occupying a special position and homogeneity is preserved on a very large scale. We show how these models, at least in their current realizations, are constrained to give small, but perhaps not negligible in certain contexts, corrections to the cosmological observables. We then examine non-Copernican models, in which the observer is close to the center of a very large void. These models can give large corrections to the observables which mimic an accelerated FLRW model. We carefully discuss the main observables and tests able to exclude them.Comment: 27 pages, 7 figures; invited contribution to CQG special issue "Inhomogeneous Cosmological Models and Averaging in Cosmology". Replaced to match the improved version accepted for publication. Appendix B and references adde

Weighed scalar averaging in LTB dust models, part I: statistical fluctuations and gravitational entropy

We introduce a weighed scalar average formalism ("q-average") for the study of the theoretical properties and the dynamics of spherically symmetric Lemaitre-Tolman-Bondi (LTB) dust models models. The "q-scalars" that emerge by applying the q-averages to the density, Hubble expansion and spatial curvature (which are common to FLRW models) are directly expressible in terms of curvature and kinematic invariants and identically satisfy FLRW evolution laws without the back-reaction terms that characterize Buchert's average. The local and non-local fluctuations and perturbations with respect to the q-average convey the effects of inhomogeneity through the ratio of curvature and kinematic invariants and the magnitude of radial gradients. All curvature and kinematic proper tensors that characterize the models are expressible as irreducible algebraic expansions on the metric and 4-velocity, whose coefficients are the q-scalars and their linear and quadratic local fluctuations. All invariant contractions of these tensors are quadratic fluctuations, whose q-averages are directly and exactly related to statistical correlation moments of the density and Hubble expansion scalar. We explore the application of this formalism to a definition of a gravitational entropy functional proposed by Hosoya et al (2004 Phys. Rev. Lett. 92 141302). We show that a positive entropy production follows from a negative correlation between fluctuations of the density and Hubble scalar, providing a brief outline on its fulfillment in various LTB models and regions. While the q-average formalism is specially suited for LTB and Szekeres models, it may provide a valuable theoretical insight on the properties of scalar averaging in inhomogeneous spacetimes in general.Comment: 27 pages in IOP format, 1 figure. Matches version accepted for publication in Classical and Quantum Gravit

Large-scale instability in interacting dark energy and dark matter fluids

If dark energy interacts with dark matter, this gives a new approach to the coincidence problem. But interacting dark energy models can suffer from pathologies. We consider the case where the dark energy is modelled as a fluid with constant equation of state parameter w. Non-interacting constant-w models are well behaved in the background and in the perturbed universe. But the combination of constant w and a simple interaction with dark matter leads to an instability in the dark sector perturbations at early times: the curvature perturbation blows up on super-Hubble scales. Our results underline how important it is to carefully analyze the relativistic perturbations when considering models of coupled dark energy. The instability that we find has been missed in some previous work where the perturbations were not consistently treated. The unstable mode dominates even if adiabatic initial conditions are used. The instability also arises regardless of how weak the coupling is. This non-adiabatic instability is different from previously discovered adiabatic instabilities on small scales in the strong-coupling regime.Comment: 15 pages, 5 figures. New reference; published versio

Large-scale instability in interacting dark energy and dark matter fluids

If dark energy interacts with dark matter, this gives a new approach to the coincidence problem. But interacting dark energy models can suffer from pathologies. We consider the case where the dark energy is modelled as a fluid with constant equation of state parameter w. Non-interacting constant-w models are well behaved in the background and in the perturbed universe. But the combination of constant w and a simple interaction with dark matter leads to an instability in the dark sector perturbations at early times: the curvature perturbation blows up on super-Hubble scales. Our results underline how important it is to carefully analyze the relativistic perturbations when considering models of coupled dark energy. The instability that we find has been missed in some previous work where the perturbations were not consistently treated. The unstable mode dominates even if adiabatic initial conditions are used. The instability also arises regardless of how weak the coupling is. This non-adiabatic instability is different from previously discovered adiabatic instabilities on small scales in the strong-coupling regime.Comment: 15 pages, 5 figures. New reference; published versio

The effects of implementing a point-of-care electronic template to prompt routine anxiety and depression screening in patients consulting for osteoarthritis (the Primary Care Osteoarthritis Trial): A cluster randomised trial in primary care

Background This study aimed to evaluate whether prompting general practitioners (GPs) to routinely assess and manage anxiety and depression in patients consulting with osteoarthritis (OA) improves pain outcomes. Methods and findings We conducted a cluster randomised controlled trial involving 45 English general practices. In intervention practices, patients aged ≥45 y consulting with OA received point-of-care anxiety and depression screening by the GP, prompted by an automated electronic template comprising five questions (a two-item Patient Health Questionnaire–2 for depression, a two-item Generalized Anxiety Disorder–2 questionnaire for anxiety, and a question about current pain intensity [0–10 numerical rating scale]). The template signposted GPs to follow National Institute for Health and Care Excellence clinical guidelines for anxiety, depression, and OA and was supported by a brief training package. The template in control practices prompted GPs to ask the pain intensity question only. The primary outcome was patient-reported current pain intensity post-consultation and at 3-, 6-, and 12-mo follow-up. Secondary outcomes included pain-related disability, anxiety, depression, and general health. During the trial period, 7,279 patients aged ≥45 y consulted with a relevant OA-related code, and 4,240 patients were deemed potentially eligible by participating GPs. Templates were completed for 2,042 patients (1,339 [31.6%] in the control arm and 703 [23.1%] in the intervention arm). Of these 2,042 patients, 1,412 returned questionnaires (501 [71.3%] from 20 intervention practices, 911 [68.0%] from 24 control practices). Follow-up rates were similar in both arms, totalling 1,093 (77.4%) at 3 mo, 1,064 (75.4%) at 6 mo, and 1,017 (72.0%) at 12 mo. For the primary endpoint, multilevel modelling yielded significantly higher average pain intensity across follow-up to 12 mo in the intervention group than the control group (adjusted mean difference 0.31; 95% CI 0.04, 0.59). Secondary outcomes were consistent with the primary outcome measure in reflecting better outcomes as a whole for the control group than the intervention group. Anxiety and depression scores did not reduce following the intervention. The main limitations of this study are two potential sources of bias: an imbalance in cluster size (mean practice size 7,397 [intervention] versus 5,850 [control]) and a difference in the proportion of patients for whom the GP deactivated the template (33.6% [intervention] versus 27.8% [control]). Conclusions In this study, we observed no beneficial effect on pain outcomes of prompting GPs to routinely screen for and manage comorbid anxiety and depression in patients presenting with symptoms due to OA, with those in the intervention group reporting statistically significantly higher average pain scores over the four follow-up time points than those in the control group. Trial registration ISRCTN registry ISRCTN4072198

Phylogenomics and the rise of the angiosperms

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods1,2. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome3,4. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins5–7. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes8. This 15-fold increase in genus-level sampling relative to comparable nuclear studies9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease