Orbit period modulation for relative motion using continuous low thrust in the two-body and restricted three-body problems

This paper presents rich new families of relative orbits for spacecraft formation flight generated through the application of continuous thrust with only minimal intervention into the dynamics of the problem. Such simplicity facilitates implementation for small, low-cost spacecraft with only position state feedback, and yet permits interesting and novel relative orbits in both two- and three-body systems with potential future applications in space-based interferometry, hyperspectral sensing, and on-orbit inspection. Position feedback is used to modify the natural frequencies of the linearised relative dynamics through direct manipulation of the system eigenvalues, producing new families of stable relative orbits. Specifically, in the Hill–Clohessy–Wiltshire frame, simple adaptations of the linearised dynamics are used to produce a circular relative orbit, frequency-modulated out-of-plane motion, and a novel doubly periodic cylindrical relative trajectory for the purposes of on-orbit inspection. Within the circular restricted three-body problem, a similar minimal approach with position feedback is used to generate new families of stable, frequency-modulated relative orbits in the vicinity of a Lagrange point, culminating in the derivation of the gain requirements for synchronisation of the in-plane and out-of-plane frequencies to yield a singly periodic tilted elliptical relative orbit with potential use as a Lunar far-side communications relay. The Δv requirements for the cylindrical relative orbit and singly periodic Lagrange point orbit are analysed, and it is shown that these requirements are modest and feasible for existing low-thrust propulsion technology

Protease-activated receptor-2 : a novel pathogenic pathway in a murine model of osteoarthritis

Osteoarthritis (OA) is a global clinical challenge for which no effective disease modifying agents currently exist. Herein we identify protease-activated receptor-2 (PAR-2) as a novel pathogenic mechanism and potential therapeutic target in OA. Experimental OA was induced in wild-type and PAR-2 deficient mice by sectioning the medial menisco-tibial ligament (MMTL), leading to development of a mild arthropathy. Cartilage degradation and increased subchondral bone formation were assessed as indicators of OA pathology. Four weeks following MMTL section, cartilage erosion and increased subchondral bone formation was evident in wild type mice but substantially reduced in PAR-2 deficient mice. Crucially, therapeutic inhibition of PAR-2 in wild type mice,using either a PAR-2 antagonist or a monoclonal antibody targeting the protease cleavage site of PAR-2, was also equally effective at reducing OA progression in vivo. PAR-2 wasupregulated in chondrocytes of wild-type but not sham-operated mice. Wild type mice showed further joint degradation eight weeks following induction of OA, but PAR-2 deficient mice were still protected. The substantial protection from pathology afforded by PAR-2 deficiency following induction of OA provides proof of concept that PAR-2 has a key role in OA and suggests this receptor as a potential therapeutic target. Osteoarthritis (OA) is a chronic disabling condition currently affecting millions globally 1 with radiological evidence of OA in approximately 80% of the population aged over 65. 2OA is characterised by cartilage degradation and increased subchondral bone formation (osteosclerosis). Despite extensive pathophysiologic investigations, clinical management has not altered significantly and comprises administration of analgesics and non-steroidal anti-inflammatory agents and recourse upon joint failure to arthroplasty. No unifying pathogenetic model exists - suggested hypotheses encompass primary cartilage metabolic dysregulation, enthesial disease together with biomechanical dysregulation. Thus far, no critical checkpoint pathway has been identified that is essential for disease progression and which might by corollary represent a valid, disease-modifying OA therapeutic target. Protease-activated receptor-2 (PAR-2) is a G-protein coupled receptor whose 'tethered' ligand is activated by serine proteases. 3 PAR-2 is present in chondrocytes in cartilage from OA patients 4, and following its activation, matrix metalloproteases (MMPs) are generated. 5 However, these previous observations are associative and do not establish the role of PAR-2 in the pathogenesis of OA. We here sought direct evidence of a causal relationship between PAR-2 expression and cartilage and bone pathology in a murine model of OA

Exact time-localized solutions in Vacuum String Field Theory

We address the problem of finding star algebra projectors that exhibit localized time profiles. We use the double Wick rotation method, starting from an Euclidean (unconventional) lump solution, which is characterized by the Neumann matrix being the conventional one for the continuous spectrum, while the inverse of the conventional one for the discrete spectrum. This is still a solution of the projector equation and we show that, after inverse Wick-rotation, its time profile has the desired localized time dependence. We study it in detail in the low energy regime (field theory limit) and in the extreme high energy regime (tensionless limit) and show its similarities with the rolling tachyon solution.Comment: 27 pages, 2 figures. v2: typos corrected, ref added, comment added in last section, to appear on NP

Extension of Earth-Moon libration point orbits with solar sail propulsion

This paper presents families of libration point orbits in the Earth-Moon system that originate from complementing the classical circular restricted three-body problem with a solar sail. Through the use of a differential correction scheme in combination with a continuation on the solar sail induced acceleration, families of Lyapunov, halo, vertical Lyapunov, Earth-centred, and distant retrograde orbits are created. As the solar sail circular restricted three-body problem is non-autonomous, a constraint defined within the differential correction scheme ensures that all orbits are periodic with the Sun’s motion around the Earth-Moon system. The continuation method then starts from a classical libration point orbit with a suitable period and increases the solar sail acceleration magnitude to obtain families of orbits that are parametrised by this acceleration. Furthermore, different solar sail steering laws are considered (both in-plane and out-of-plane, and either fixed in the synodic frame or fixed with respect to the direction of sunlight), adding to the wealth of families of solar sail enabled libration point orbits presented. Finally, the linear stability properties of the generated orbits are investigated to assess the need for active orbital control. It is shown that the solar sail induced acceleration can have a positive effect on the stability of some orbit families, especially those at the L2 point, but that it most often (further) destabilises the orbit. Active control will therefore be needed to ensure long-term survivability of these orbits

Constraining the electric charges of some astronomical bodies in Reissner-Nordstrom spacetimes and generic r^-2-type power-law potentials from orbital motions

We put model-independent, dynamical constraints on the net electric charge Q of some astronomical and astrophysical objects by assuming that their exterior spacetimes are described by the Reissner-Nordstroem metric, which induces an additional potential U_RN \propto Q^2 r^-2. Our results extend to other hypothetical power-law interactions inducing extra-potentials U_pert = r^-2 as well (abridged).Comment: LaTex2e, 16 pages, 3 figures, no tables, 128 references. Version matching the one at press in General Relativity and Gravitation (GRG). arXiv admin note: substantial text overlap with arXiv:1112.351

Accelarated immune ageing is associated with COVID-19 disease severity

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01). Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. Funding: UK Research and Innovation and National Institute for Health Research