Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding: Vicore Pharma AB and LifeArc, UK

Higher-Spin Interactions: four-point functions and beyond

In this work we construct an infinite class of four-point functions for massless higher-spin fields in flat space that are consistent with the gauge symmetry. In the Lagrangian picture, these reflect themselves in a peculiar non-local nature of the corresponding non-abelian higher-spin couplings implied by the Noether procedure that starts from the fourth order. We also comment on the nature of the colored spin-2 excitation present both in the open string spectrum and in the Vasiliev system, highlighting how some aspects of String Theory appear to reflect key properties of Field Theory that go beyond its low energy limit. A generalization of these results to n-point functions, fermions and mixed-symmetry fields is also addressed.Comment: 66 pages, 10 figures, 1 table, LaTex. Several statements clarified. Final version to appear in JHE

Superconformal symmetry and maximal supergravity in various dimensions

In this paper we explore the relation between conformal superalgebras with 64 supercharges and maximal supergravity theories in three, four and six dimensions using twistorial oscillator techniques. The massless fields of N=8 supergravity in four dimensions were shown to fit into a CPT-self-conjugate doubleton supermultiplet of the conformal superalgebra SU(2,2|8) a long time ago. We show that the fields of maximal supergravity in three dimensions can similarly be fitted into the super singleton multiplet of the conformal superalgebra OSp(16|4,R), which is related to the doubleton supermultiplet of SU(2,2|8) by dimensional reduction. Moreover, we construct the ultra-short supermultiplet of the six-dimensional conformal superalgebra OSp(8*|8) and show that its component fields can be organized in an on-shell superfield. The ultra-short OSp(8*|8) multiplet reduces to the doubleton supermultiplet of SU(2,2|8) upon dimensional reduction. We discuss the possibility of a chiral maximal (4,0) six-dimensional supergravity theory with USp(8) R-symmetry that reduces to maximal supergravity in four dimensions and is different from six-dimensional (2,2) maximal supergravity, whose fields cannot be fitted into a unitary supermultiplet of a simple conformal superalgebra. Such an interacting theory would be the gravitational analog of the (2,0) theory.Comment: 54 pages, PDFLaTeX, Section 5 and several references added. Version accepted for publication in JHE

Gauge-invariant correlation functions in light-cone superspace

We initiate a study of correlation functions of gauge-invariant operators in N=4 super Yang-Mills theory using the light-cone superspace formalism. Our primary aim is to develop efficient methods to compute perturbative corrections to correlation functions. This analysis also allows us to examine potential subtleties which may arise when calculating off-shell quantities in light-cone gauge. We comment on the intriguing possibility that the manifest N=4 supersymmetry in this approach may allow for a compact description of entire multiplets and their correlation functions.Comment: 35 pages, several figure

Clustering and forecasting of dissolved oxygen concentration on a river basin

The aim of this contribution is to combine statistical methodologies to geographically classify homogeneous groups of water quality monitoring sites based on similarities in the temporal dynamics of the dissolved oxygen (DO) concentration, in order to obtain accurate forecasts of this quality variable. Our methodology intends to classify the water quality monitoring sites into spatial homogeneous groups, based on the DO concentration, which has been selected and considered relevant to characterize the water quality. We apply clustering techniques based on Kullback Information, measures that are obtained in the state space modelling process. For each homogeneous group of water quality monitoring sites we model the DO concentration using linear and state space models, which incorporate tendency and seasonality components in different ways. Both approaches are compared by the mean squared error (MSE) of forecasts

Higher-Spin Fermionic Gauge Fields and Their Electromagnetic Coupling

We study the electromagnetic coupling of massless higher-spin fermions in flat space. Under the assumptions of locality and Poincare invariance, we employ the BRST-BV cohomological methods to construct consistent parity-preserving off-shell cubic 1-s-s vertices. Consistency and non-triviality of the deformations not only rule out minimal coupling, but also restrict the possible number of derivatives. Our findings are in complete agreement with, but derived in a manner independent from, the light-cone-formulation results of Metsaev and the string-theory-inspired results of Sagnotti-Taronna. We prove that any gauge-algebra-preserving vertex cannot deform the gauge transformations. We also show that in a local theory, without additional dynamical higher-spin gauge fields, the non-abelian vertices are eliminated by the lack of consistent second-order deformations.Comment: 44 pages; references added, minor changes made, to appear in JHE

Maxwell-like Lagrangians for higher spins

We show how implementing invariance under divergence-free gauge transformations leads to a remarkably simple Lagrangian description of massless bosons of any spin. Our construction covers both flat and (A)dS backgrounds and extends to tensors of arbitrary mixed-symmetry type. Irreducible and traceless fields produce single-particle actions, while whenever trace constraints can be dispensed with the resulting Lagrangians display the same reducible, multi-particle spectra as those emerging from the tensionless limit of free open-string field theory. For all explored options the corresponding kinetic operators take essentially the same form as in the spin-one, Maxwell case.Comment: 77 pages, revised version. Erroneous interpretation and proof of the gauge-fixing procedure for mixed-symmetry fields corrected. As a consequence, the mixed-symmetry, one-particle Lagrangians are to be complemented with conditions on the divergences of the fields; all other conclusions unchanged. Additional minor changes including references added. To appear in JHE

The experience of brace treatment in children/adolescents with scoliosis

BACKGROUND: Idiopathic scoliosis is a chronic illness with several different braces used for its treatment. Brace treatment during childhood/adolescence can produce stress. There are studies supporting that it can decrease body-image perception while other studies support that it has no such effect. The purpose of this study was to explore the experience of brace treatment in children/adolescents with scoliosis. The aim was to investigate which feelings are created by the bracing experience in children/adolescents with scoliosis and what are the children/adolescents' with scoliosis opinions of the support provided to them by health-care professionals and by their families. METHODS: We conducted interviews with the help of a semi-structured interview guide in order to address the topic of the experience of brace treatment. A convenient sample of twelve children and adolescents with scoliosis was selected from patients attending follow-up appointments at the Outpatient Scoliosis Clinics of two Greek hospitals. The data was analysed using the method of content analysis. RESULTS: Patients in the sample were 10–16 years old and they were mainly females (71%). Almost all of the participants reported having to deal with stress, denial, fear, anger, and shame. They were satisfied with the information they received regarding their condition and therapy. However, the information was not accompanied by support from the health care professionals. They reported that they were receiving support mainly from their families, friends, and classmates. CONCLUSION: The present study is contributing to the development of a better understanding of significant issues related to the experience of bracing therapy. It is clear that scoliosis children/adolescents have to be provided with support during the long period of bracing. It is apparent that those children/adolescents have unmet needs for care and health professionals and policy makers should try to find a way to address those needs

Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer

The generation of antitumour immunity depends on the nature of dendritic cell (DC)–tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy

Quantification of Circadian Rhythms in Single Cells

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber)