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Background\ud \ud There is an urgent clinical need for evidence-based psychosocial interventions for people with mild dementia. We aimed to determine the clinical benefits and cost-effectiveness of Journeying through Dementia (JtD), an intervention designed to promote wellbeing and independence in people with mild dementia.\ud \ud \ud \ud Methods\ud \ud We did a single-blind, parallel group, individually randomised, phase 3 trial at 13 National Health Service sites across England. People with mild dementia (Mini-Mental State Examination score of ≥18) who lived in the community were eligible for inclusion. Patients were centrally randomly assigned (1:1) to receive the JtD intervention plus standard care (JtD group) or standard care only (standard care group). Randomisation was stratified by study site. The JtD intervention included 12 group and four one-to-one sessions, delivered in the community at each site. The primary endpoint was Dementia Related Quality of Life (DEMQOL) 8 months after randomisation, assessed according to the intention-to-treat principle. Only outcome assessors were masked to group assignment. A cost-effectiveness analysis reported cost per quality-adjusted life-year (QALY) from a UK NHS and social care perspective. The study is registered with ISRCTN, ISRCTN17993825.\ud \ud \ud \ud Findings\ud \ud Between Nov 30, 2016, and Aug 31, 2018, 1183 patients were screened for inclusion, of whom 480 (41%) participants were randomly assigned: 241 (50%) to the JtD group and 239 (50%) to the standard care group. Intervention adherence was very good: 165 (68%) of 241 participants in the JtD group attended at least ten of the 16 sessions. Mean DEMQOL scores at 8 months were 93·3 (SD 13·0) for the JtD group and 91·9 (SD 14·6) for the control group. Difference in means was 0·9 (95% CI –1·2 to 3·0; p=0·38) after adjustment for covariates, lower than that identified as clinically meaningful. Incremental cost per QALY ranged from £88 000 to –£205 000, suggesting that JtD was not cost-effective. Unrelated serious adverse events were reported by 40 (17%) patients in the JtD group and 35 (15%) patients in the standard care group.\ud \ud \ud \ud Interpretation\ud \ud In common with other studies, the JtD intervention was not proven effective. However, this complex trial successfully recruited and retained people with dementia without necessarily involving carers. Additionally, people with dementia were actively involved as participants and study advisers throughout. More research into methods of measuring small, meaningful changes in this population is needed. Questions remain regarding how services can match the complex, diverse, and individual needs of people with mild dementia, and how interventions to meet such needs can be delivered at scale.\ud \ud \ud \ud Funding\ud \ud UK National Institute of Health Research Health Technology Assessment Programme.

Methods: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before DAA therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed).Results: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35±4 ms), transverse relaxation time (T2, 2.5±0.8 ms; T2* 3.0±0.7 ms) and liver perfusion (28.1±19.7ml/100g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or SMA blood flow.Conclusion: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2, T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms.

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Amongst the controls determining polarity are the PAR proteins, PAR6/aPKCiota-PAR3, regulating both known and unknown effectors. Here we identify FARP2 as a "RIPR" motif dependent partner and substrate of aPKCiota that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain-Kinase\ud domain interaction and detachment promoted by aPKCiota dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42 consistent with upstream regulation of the polarising PAR6-aPKCiota complex. However, it is shown that aPKCiota acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCiota FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCiota and other Cdc42 effectors.\ud \ud Ahmed , Yixiao , Mathias , Philippe , Ray S. , Selene K. Roberts, Chris Tynan, Roger George, Svend Kjaer, Marisa L. Martin-Fernandez, Barry J. Thompson, Neil Q. McDonald, Peter J. Parker

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.