Lyophilization to enable distribution of ChAdOx1 and ChAdOx2 adenovirus-vectored vaccines without refrigeration

Distribution of vaccines which require refrigerated or frozen storage can be challenging and expensive. The adenovirus vector platform has been widely used for COVID-19 vaccines while several further candidate vaccines using the platform are in clinical development. In current liquid formulations, adenoviruses require distribution at 2-8 °C. The development of formulations suitable for ambient temperature distribution would be advantageous. Previous peer-reviewed reports of adenovirus lyophilization are relatively limited. Here, we report the development of a formulation and process for lyophilization of simian adenovirus-vectored vaccines based on the ChAdOx1 platform. We describe the iterative selection of excipients using a design of experiments approach, and iterative cycle improvement to achieve both preservation of potency and satisfactory cake appearance. The resulting method achieved in-process infectivity titre loss of around 50%. After drying, there was negligible further loss over a month at 30 °C. Around 30% of the predrying infectivity remained after a month at 45 °C. This performance is likely to be suitable for 'last leg' distribution at ambient temperature. This work may also facilitate the development of other product presentations using dried simian adenovirus-vectored vaccines

Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Policy Coherence in US Tobacco Control: Beyond FDA Regulation

Joshua Yang and Thomas Novotny explore whether the US government can develop and implement a coherent policy agenda to reduce tobacco-related morbidity and mortality

Social interactions through the eyes of macaques and humans

Group-living primates frequently interact with each other to maintain social bonds as well as to compete for valuable resources. Observing such social interactions between group members provides individuals with essential information (e.g. on the fighting ability or altruistic attitude of group companions) to guide their social tactics and choice of social partners. This process requires individuals to selectively attend to the most informative content within a social scene. It is unclear how non-human primates allocate attention to social interactions in different contexts, and whether they share similar patterns of social attention to humans. Here we compared the gaze behaviour of rhesus macaques and humans when free-viewing the same set of naturalistic images. The images contained positive or negative social interactions between two conspecifics of different phylogenetic distance from the observer; i.e. affiliation or aggression exchanged by two humans, rhesus macaques, Barbary macaques, baboons or lions. Monkeys directed a variable amount of gaze at the two conspecific individuals in the images according to their roles in the interaction (i.e. giver or receiver of affiliation/aggression). Their gaze distribution to non-conspecific individuals was systematically varied according to the viewed species and the nature of interactions, suggesting a contribution of both prior experience and innate bias in guiding social attention. Furthermore, the monkeys’ gaze behavior was qualitatively similar to that of humans, especially when viewing negative interactions. Detailed analysis revealed that both species directed more gaze at the face than the body region when inspecting individuals, and attended more to the body region in negative than in positive social interactions. Our study suggests that monkeys and humans share a similar pattern of role-sensitive, species- and context-dependent social attention, implying a homologous cognitive mechanism of social attention between rhesus macaques and humans

Transiting Disintegrating Planetary Debris around WD 1145+017

More than a decade after astronomers realized that disrupted planetary material likely pollutes the surfaces of many white dwarf stars, the discovery of transiting debris orbiting the white dwarf WD 1145+017 has opened the door to new explorations of this process. We describe the observational evidence for transiting planetary material and the current theoretical understanding (and in some cases lack thereof) of the phenomenon.Comment: Invited review chapter. Accepted March 23, 2017 and published October 7, 2017 in the Handbook of Exoplanets. 15 pages, 10 figure

The attachments of the anteromedial and posterolateral fibre bundles of the anterior cruciate ligament: Part 1: tibial attachment.

Accepted versio

Carbonatites and Alkaline Igneous Rocks in Post-Collisional Settings: Storehouses of Rare Earth Elements

This is the final version. Available on open access from Springer via the DOI in this recordThe rare earth elements (REE) are critical raw materials for much of modern technology, particularly renewable energy infrastructure and electric vehicles that are vital for the energy transition. Many of the world’s largest REE deposits occur in alkaline rocks and carbonatites, which are found in intracontinental, rift-related settings, and also in syn- to post-collisional settings. Post-collisional settings host significant REE deposits, such as those of the Mianning-Dechang belt in China. This paper reviews REE mineralisation in syn- to post-collisional alkaline-carbonatite complexes worldwide, in order to demonstrate some of the key physical and chemical features of these deposits. We use three examples, in Scotland, Namibia, and Turkey, to illustrate the structure of these systems. We review published geochemical data and use these to build up a broad model for the REE mineral system in post-collisional alkaline-carbonatite complexes. It is evident that immiscibility of carbonate-rich magmas and fluids plays an important part in generating mineralisation in these settings, with REE, Ba and F partitioning into the carbonate-rich phase. The most significant REE mineralisation in post-collisional alkaline-carbonatite complexes occurs in shallow-level, carbothermal or carbonatite intrusions, but deeper carbonatite bodies and associated alteration zones may also have REE enrichment.European Union Horizon 2020Natural Environment Research Council (NERC