Further results on non-diagonal Bianchi type III vacuum metrics

We present the derivation, for these vacuum metrics, of the Painlev\'e VI equation first obtained by Christodoulakis and Terzis, from the field equations for both minkowskian and euclidean signatures. This allows a complete discussion and the precise connection with some old results due to Kinnersley. The hyperk\"ahler metrics are shown to belong to the Multi-Centre class and for the cases exhibiting an integrable geodesic flow the relevant Killing tensors are given. We conclude by the proof that for the Bianchi B family, excluding type III, there are no hyperk\"ahler metrics.Comment: 21 pages, no figure

The General Solution of Bianchi Type VIIhVII_h Vacuum Cosmology

The theory of symmetries of systems of coupled, ordinary differential equations (ODE) is used to develop a concise algorithm in order to obtain the entire space of solutions to vacuum Bianchi Einstein Field Equations (EFEs). The symmetries used are the well known automorphisms of the Lie algebra for the corresponding isometry group of each Bianchi Type, as well as the scaling and the time re-parametrization symmetry. The application of the method to Type VII_h results in (a) obtaining the general solution of Type VII_0 with the aid of the third Painlev\'{e} transcendental (b) obtaining the general solution of Type $VII_h$ with the aid of the sixth Painlev\'{e} transcendental (c) the recovery of all known solutions (six in total) without a prior assumption of any extra symmetry (d) The discovery of a new solution (the line element given in closed form) with a G_3 isometry group acting on T_3, i.e. on time-like hyper-surfaces, along with the emergence of the line element describing the flat vacuum Type VII_0 Bianchi Cosmology.Comment: latex2e source file, 27 pages, 2 tables, no fiure

Analytic and Asymptotic Methods for Nonlinear Singularity Analysis: a Review and Extensions of Tests for the Painlev\'e Property

The integrability (solvability via an associated single-valued linear problem) of a differential equation is closely related to the singularity structure of its solutions. In particular, there is strong evidence that all integrable equations have the Painlev\'e property, that is, all solutions are single-valued around all movable singularities. In this expository article, we review methods for analysing such singularity structure. In particular, we describe well known techniques of nonlinear regular-singular-type analysis, i.e. the Painlev\'e tests for ordinary and partial differential equations. Then we discuss methods of obtaining sufficiency conditions for the Painlev\'e property. Recently, extensions of \textit{irregular} singularity analysis to nonlinear equations have been achieved. Also, new asymptotic limits of differential equations preserving the Painlev\'e property have been found. We discuss these also.Comment: 40 pages in LaTeX2e. To appear in the Proceedings of the CIMPA Summer School on "Nonlinear Systems," Pondicherry, India, January 1996, (eds) B. Grammaticos and K. Tamizhman

Scaled limit and rate of convergence for the largest eigenvalue from the generalized Cauchy random matrix ensemble

In this paper, we are interested in the asymptotic properties for the largest eigenvalue of the Hermitian random matrix ensemble, called the Generalized Cauchy ensemble $GCy$, whose eigenvalues PDF is given by $$\textrm{const}\cdot\prod_{1\leq j<k\leq N}(x_j-x_k)^2\prod_{j=1}^N (1+ix_j)^{-s-N}(1-ix_j)^{-\bar{s}-N}dx_j,$$where $s$ is a complex number such that $\Re(s)>-1/2$ and where $N$ is the size of the matrix ensemble. Using results by Borodin and Olshanski \cite{Borodin-Olshanski}, we first prove that for this ensemble, the largest eigenvalue divided by $N$ converges in law to some probability distribution for all $s$ such that $\Re(s)>-1/2$. Using results by Forrester and Witte \cite{Forrester-Witte2} on the distribution of the largest eigenvalue for fixed $N$, we also express the limiting probability distribution in terms of some non-linear second order differential equation. Eventually, we show that the convergence of the probability distribution function of the re-scaled largest eigenvalue to the limiting one is at least of order $(1/N)$.Comment: Minor changes in this version. Added references. To appear in Journal of Statistical Physic

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

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 hospitalization2,3,4 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

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using intensity modulated radiotherapy.

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using IMRT. The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose-volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7-31.2% depending on the alpha/beta ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4-27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions