ABSTRACT
Specialist weaning units (SWUs) aim to liberate patients with complex weaning failure from mechanical ventilation and facilitate their discharge from the ICU. This retrospective service evaluation reports the outcomes of a SWU at Wythenshawe Hospital, Manchester between 2017 and 2019. In total, 75.0% (n = 33/44) of patients survived to hospital discharge. Of these patients, 72.7% (n = 24/33) were self-ventilating. Overall, 1-year survival was 68.2% (n = 30/44), whilst 5-year survival was 52.3% (n = 23/44). Whilst this study is relatively small, these findings are encouraging and further support the case for SWUs.
ABSTRACT
One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aß) protein in amyloid plaques in the brain. The Aß peptide exists in several forms, including full-length Aß1-42 and Aß1-40 - and the N-truncated species, pyroglutamate Aß3-42 and Aß4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aß species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aß3-14, we identified a novel pseudo ß-hairpin structure in the N-terminal region of Aß and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aß1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aß, which offers new routes for active and passive immunisation against AD.