Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

REFLECTION AND REFRACTION OF AN OBLIQUELY INCIDENT SHEAR WAVE AT A SOLID-NEMATIC INTERFACE

Nous présentons un calcul détaillé de la réflexion et de la réfraction des ondes de cisaillement en incidence oblique sur un interface solide-nématique pour les trois géométries discutées par Martinoty et Candau [1]. Contrairement à l'analyse donnée par ces auteurs, lorsque l'inclinaison du détecteur en surface est parallèle au mouvement induit, nous trouvons dans le nématique trois modes plutôt que deux. Pour les deux autres géométries, nous trouvons simplement deux modes mais certains aspects de notre calcul sont nouveaux. Néanmoins, dans les trois cas, les résultats obtenus se réduisent à ceux donnés par Martinoty et Candau moyennant des approximations raisonnables.We present a detailed calculation of reflection and refraction of obliquely incident shear waves at a solid-nematic interface for the three surface alignments discussed by Martinoty and Candau [l]. In contrast with the analysis given by these authors, when the surface alignment is parallel to the induced motion, our solution for the perturbation in the nematic consists of three modes rather than two. While the solutions for the remaining two cases each consist of only two modes, certain aspects of our calculation are new. However, for all three cases, the results obtained reduce under reasonable approximations to those given by Martinoty and Candau

Thermal instability in a sample of nematic liquid crystal contained in a rotating annulus

Continuum theory is employed to investigate the stability of a sample of nematic liquid crystal contained between two long, concentric, circular cylinders, rotating with constant angular velocity about the cylindrical axis, when subjected to a radial thermal gradient. We consider the arrangement in which the anisotropic axis of the material is initially uniformly aligned parallel to the axis of the cylinders. Using Galerkin and ortho-normalization methods, both positive and negative thermal gradient thresholds are predicted at which the onset of a convective instability is possible. The effects of angular velocity and the strength of an applied magnetic field are also examined. These theoretical results suggest an experimental possibility of observing the small wavenumber instability predicted by Velarde and Zuniga [1] in the Rayleigh-Bénard problem for nematics.Nous employons la théorie des milieux continus pour étudier la stabilité d'un échantillon de cristal liquide nématique sous faible épaisseur contenu entre deux longs cylindres concentriques en rotation à vitesse angulaire constante le long de leur axe, et soumis à un gradient de température radial. Nous considérons le cas d'un matériau initialement aligné parallèlement à l'axe des cylindres. Utilisant les méthodes de Galerkin et d'orthonormalisation, nous déterminons les seuils positif et négatif des gradients thermiques pour lesquels l'apparition d'une instabilité de convection est possible. Les effets de la vitesse angulaire et d'un champ magnétique appliqué sont également examinés. Nous montrons qu'il est possible d'observer l'instabilité à petit nombre d'onde que Velarde et Zuniga [1] ont proposée dans le cas du problème de Rayleigh-Bénard pour les nématiques

Developing biosafety risk hypotheses for invertebrates exposed to GM plants using conceptual food webs: A case study with elevated triacylglyceride levels in ryegrass

Regulators are acutely aware of the need for meaningful risk assessments to support decisions on the safety of GM crops to non-target invertebrates in determining their suitability for field release. We describe a process for developing appropriate, testable risk hypotheses for invertebrates in agroecosystems that might be exposed to plants developed by GM and future novel technologies. An existing model (PRONTI) generates a ranked list of invertebrate species for biosafety testing by accessing a database of biological, ecological and food web information about species which occur in cropping environments and their potential interactions with a particular stressor (Eco Invertebase). Our objective in this contribution is to explore and further utilise these resources to assist in the process of problem formulation by identifying potentially significant effects of the stressor on the invertebrate community and the ecosystem services they provide. We propose that for high ranking species, a conceptual food web using information in Eco Invertebase is constructed, and using an accepted regulatory risk analysis framework, the likelihood of risk, and magnitude of impact for each link in the food web is evaluated. Using as filters only those risks evaluated as likely to extremely likely, and the magnitude of an effect being considered as moderate to massive, the most significant potential effects can be identified. A stepwise approach is suggested to develop a sequence of appropriate tests. The GM ryegrass plant used as the “stressor” in this study has been modified to increase triacylglyceride levels in foliage by 100% to increase the metabolisable energy content of forage for grazing animals. The high-ranking “test” species chosen to illustrate the concept are New Zealand native species Wiseana cervinata (Walker) (Lepidoptera: Hepialidae), Persectania aversa (Walker) (Lepidoptera: Noctuidae), and the self-introduced grey field slug, Deroceras reticulatum (Müller)