Promoting Independence in Dementia (PRIDE): A Feasibility Randomized Controlled Trial

Background: There is a need for interventions to foster and maintain independence for people with dementia to support community living, improve morale, and reduce stigma. We investigated a social intervention to promote living well and enhance independence for people with mild dementia.Methods: In this two arm parallel group, feasibility RCT at six sites in England, participants were randomized (1:1) to the PRIDE intervention (encompassing social, physical, and cognitive domains supported by a facilitator over three sessions) compared to usual care only. The main objective was to determine the feasibility of a main trial with respect to measures of recruitment, retention, and adherence to the intervention.Results: During a 7-month period, 402 people were invited to the trial, 148 were screened (37%, 95% confidence interval (CI)=32– 42%), 137 were eligible at pre-consent, 94 consented to the trial (69% of those eligible, 95% CI=60– 76%), and 92 were randomized (46 to each group). Of those allocated to the intervention, 42 (91%) received at least one of three intervention sessions. Outcome assessment follow-up visits were completed for 73 participants at 6 months (79%, 95% CI=70– 87%), and this was similar for both groups.Conclusion: A large multi-center trial of the PRIDE intervention in community-dwelling people with mild dementia is feasible using systematic recruitment strategies. The intervention was successfully delivered and well received by participants. Findings from this study will be used to refine the design and processes for a definitive RCT.Trial Registration: ISRCTN, ISRCTN11288961, registered on 23 October 2018

Global assessment of impacts on migration and security issues

HELIX - High-End cLimate Impacts and eXtreme

Promoting Independence in Dementia (PRIDE): protocol for a feasibility randomised controlled trial.

BACKGROUND: Memory services often see people with early stage dementia who are largely independent and able to participate in community activities but who run the risk of reducing activities and social networks. PRIDE is a self-management intervention designed to promote living well and enhance independence for people with mild dementia. This study aims to examine the feasibility of conducting a definitive randomised trial comparing the clinical and cost-effectiveness of the PRIDE intervention offered in addition to usual care or with usual care alone. METHODS/DESIGN: PRIDE is a parallel, two-arm, multicentre, feasibility, randomised controlled trial (RCT). Eligible participants aged 18 or over who have mild dementia (defined as a score of 0.5 or 1 on the Clinical Dementia Rating Scale) who can participate in the intervention and provide informed consent will be randomised (1:1) to treatment with the PRIDE intervention delivered in addition to usual care, or usual care only. Participants will be followed-up at 3 and 6 month's post-randomisation. There will be an option for a supporter to join each participant. Each supporter will be provided with questionnaires at baseline and follow-ups at 3 to 6 months. Embedded qualitative research with both participants and supporters will explore their perspectives on the intervention investigating a range of themes including acceptability and barriers and facilitators to delivery and participation. The feasibility of conducting a full RCT associated with participant recruitment and follow-up of both conditions, intervention delivery including the recruitment, training, retention of PRIDE trained facilitators, clinical outcomes, intervention and resource use costs and the acceptability of the intervention and study related procedures will be examined. DISCUSSION: This study will assess whether a definitive randomised trial comparing the clinical and cost-effectiveness of whether the PRIDE intervention offered in addition to usual care is feasible in comparison to usual care alone, and if so, will provide data to inform the design and conduct of a future trial. TRIAL REGISTRATION: ISRCTN, ISRCTN11288961, registered on 23 October 2019, http://www.isrctn.com/ISRCTN12345678 Protocol V2.1 dated 19 June 2019

Changes in climate extremes, fresh water availability and vulnerability to food insecurity projected at 1.5° C and 2° C global warming with a higher-resolution global climate model

We projected changes in weather extremes, hydrological impacts and vulnerability to food insecurity at global warming of 1.5°C and 2°C relative to pre-industrial, using a new global atmospheric general circulation model HadGEM3A-GA3.0 driven by patterns of sea-surface temperatures and sea ice from selected members of the 5th Coupled Model Intercomparison Project (CMIP5) ensemble, forced with the RCP8.5 concentration scenario. To provide more detailed representations of climate processes and impacts, the spatial resolution was N216 (approx. 60 km grid length in mid-latitudes), a higher resolution than the CMIP5 models. We used a set of impacts-relevant indices and a global land surface model to examine the projected changes in weather extremes and their implications for freshwater availability and vulnerability to food insecurity. Uncertainties in regional climate responses are assessed, examining ranges of outcomes in impacts to inform risk assessments. Despite some degree of inconsistency between components of the study due to the need to correct for systematic biases in some aspects, the outcomes from different ensemble members could be compared for several different indicators. The projections for weather extremes indices and biophysical impacts quantities support expectations that the magnitude of change is generally larger for 2°C global warming than 1.5°C. Hot extremes become even hotter, with increases being more intense than seen in CMIP5 projections. Precipitation-related extremes show more geographical variation with some increases and some decreases in both heavy precipitation and drought. There are substantial regional uncertainties in hydrological impacts at local scales due to different climate models producing different outcomes. Nevertheless, hydrological impacts generally point towards wetter conditions on average, with increased mean river flows, longer heavy rainfall events, particularly in South and East Asia with the most extreme projections suggesting more than a doubling of flows in the Ganges at 2°C global warming. Some areas are projected to experience shorter meteorological drought events and less severe low flows, although longer droughts and/or decreases in low flows are projected in many other areas, particularly southern Africa and South America. Flows in the Amazon are projected to decline by up to 25%. Increases in either heavy rainfall or drought events imply increased vulnerability to food insecurity, but if global warming is limited to 1.5°C, this vulnerability is projected to remain smaller than at 2°C global warming in approximately 76% of developing countries. At 2°C, four countries are projected to reach unprecedented levels of vulnerability to food insecurity. This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’

PKA Phosphorylation of NDE1 Is DISC1/PDE4 Dependent and Modulates Its Interaction with LIS1 and NDEL1

Nuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE-like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite out-growth. NDE1/LIS1/NDEL1 interacts with Disrupted in Schizophrenia 1 (DISC1) and the cAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by cAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1–LIS1 and NDE1–NDEL1 interactions, which we confirm experimentally. DISC1–PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1–PDE4 modulated and likely to regulate its neural functions

Disc1 variation leads to specific alterations in adult neurogenesis

Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain

DISC1 at 10: connecting psychiatric genetics and neuroscience

Psychiatric genetics research, as exemplified by the DISC1 gene, aspires to inform on mental health etiology and to suggest improved strategies for intervention. DISC1 was discovered in 2000 through the molecular cloning of a chromosomal translocation that segregated with a spectrum of major mental illnesses in a single large Scottish family. Through in vitro experiments and mouse models, DISC1 has been firmly established as a genetic risk factor for a spectrum of psychiatric illness. As a consequence of its protein scaffold function, the DISC1 protein impacts on many aspects of brain function, impacting both neurosignalling and neurodevelopment. DISC1 is a pathfinder for understanding psychopathology, brain development, signaling and circuitry. Though much remains to be learnt and understood, potential targets for drug development are starting to emerge, and in this review, we will discuss the 10 years of research that has helped us understand key roles of DISC1 in psychiatric disease

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

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

NDE1 in the DISC1 pathway : interactions of schizophrenia-related proteins

The Disrupted-In-Schizophrenia 1 (DISC1) gene is one of the most established risk genes for psychiatric illness currently being studied, having originally been identified as being directly disrupted by a balanced chromosomal translocation that cosegregates with schizophrenia and other major mental illness a large Scottish family. The DISC1 protein is believed to act as a molecular scaffold within the cell, binding to a large number of other proteins. Three of these protein interactors, Phosphodiesterase 4B (PDE4B), Nuclear Distribution Factor E (Aspergillus nidulans)-homologue 1 (NDE1) and NDE-Like 1 (NDEL1) all have evidence implicating them as schizophrenia-related proteins in their own right. NDE1 and NDEL1 are highly similar proteins which are known to play cellular roles including microtubule function and mitosis. Their orthologues have also been shown to be important in neurodevelopment within the mouse brain. To date, most work in the literature has investigated NDEL1, with few focusing on NDE1. In the thesis, I first seek to establish a basic biology for NDE1 by the identification of splice variants expressed in the brain, establishing cellular localisation patterns within the cell and investigating NDE1 multimerisation. The relationship between NDE1 and NDEL1 is also investigated, with the two being found to form complexes together and to have partially over-lapping expression patterns within the cell. That NDE1 and DISC1 directly interact is confirmed. The relationship between NDE1 and PDE4B is then investigated, with the two proteins found to complex within the cell. Additionally, it is shown that NDE1 can be phosphorylated by protein kinase A (PKA). This kinase is cAMP dependant, and is thus indirectly regulated by the cAMP-degrading action of PDE4B protein. Attempts to map and analyse the effect of this phosphorylation on NDE1 are made.EThOS - Electronic Theses Online ServiceGBUnited Kingdo