Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Plasma REST: A novel candidate biomarker of Alzheimer\u27s disease is modified by psychological intervention in an at-risk population

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention—mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Indoor Nature Interventions for Health and Wellbeing of Older Adults in Residential Settings: A Systematic Review.

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.BACKGROUND AND OBJECTIVES: Having contact with nature can be beneficial for health and wellbeing, but many older adults face barriers with getting outdoors. We conducted a systematic review of quantitative studies on health and wellbeing impacts of indoor forms of nature (both real and simulated/artificial), for older adults in residential settings. RESEARCH DESIGN AND METHODS: Search terms relating to older adults and indoor nature were run in 13 scientific databases (MEDLINE, CINAHL, AgeLine, Environment Complete, AMED, PsychINFO, EMBASE, HMIC, PsychARTICLES, Global Health, Web of Knowledge, Dissertations and Theses Global, and ASSIA). We also pursued grey literature, global clinical trials registries, and a range of supplementary methods. RESULTS: Of 6,131 articles screened against eligibility criteria, 26 studies were accepted into the review, and were quality-appraised using the Effective Public Health Practice Project (EPHPP) tool. The participants were 930 adults aged over 60. Nature interventions and health/wellbeing outcomes were heterogeneous, which necessitated a narrative synthesis. The evidence base was generally weak, with 18 of 26 studies having a high risk of bias. However, several higher-quality studies found indoor gardening and horticulture programs were effective for cognition, psychological wellbeing, social outcomes, and life satisfaction. DISCUSSION AND IMPLICATIONS: There is inconsistent evidence that indoor nature exposures are beneficial for older care residents. We expect that successful interventions were, at least partly, facilitating social interaction, supporting feelings of autonomy/control, and promoting skill development, that is, factors not necessarily associated with nature per se. Higher-quality studies with improved reporting standards are needed to further elucidate these mechanisms.European CommissionNational Institute for Health Research (NIHR

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Levels of State and Trait Anxiety in Patients Referred to Ophthalmology by Primary Care Clinicians: A Cross Sectional Study

Purpose There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale. Design Cross sectional study. Participants and Controls 322 participants and 80 control participants. Methods State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality. Main Outcome Measure Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory. Results State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p0.1). Rasch analysis highlighted that the questionnaire results needed to be split into “anxiety-absent” and “anxiety-present” items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls. Conclusions State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

'Overnight, things changed. Suddenly, we were in it': a qualitative study exploring how surgical teams mitigated risks of COVID-19.

OBJECTIVES: COVID-19 presents a risk of infection and transmission for operating theatre teams. Guidelines to protect patients and staff emerged and changed rapidly based on expert opinion and limited evidence. This paper presents the experiences and innovations developed by international surgical teams during the early stages of the pandemic to attempt to mitigate risk. DESIGN: In-depth, semistructured interviews were audio recorded, transcribed and analysed thematically using methods of constant comparison. PARTICIPANTS: 43 participants, including surgeons from a range of specialties (primarily general surgery, otolaryngology, neurosurgery, cardiothoracic and ophthalmology), anaesthetists and those in nursing roles. SETTING: The UK, Italy, Spain, the USA, China and New Zealand between March and May 2020. RESULTS: Surgical teams sought to mitigate COVID-19 risks by modifying their current practice with an abundance of strategies and innovations. Communication and teamwork played an integral role in how teams adapted, although participants reflected on the challenges of having to improvise in real time. Uncertainties remained about optimal surgical practice and there were significant tensions where teams were forced to balance what was best for patients while contemplating their own safety. CONCLUSIONS: The perceptions of risks during a pandemic such as COVID-19 can be complex and context dependent. Management of these risks in surgery must be driven by evidence-based practice resulting from a pragmatic and novel approach to collation of global evidence. The context of surgery has changed dramatically, and surgical teams have developed a plethora of innovations. There is an urgent need for high-quality evidence to inform surgical practice that optimises the safety of both patients and healthcare professionals as the COVID-19 pandemic unfolds

SUPPA2:fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions

Supplementary methods. (PDF 315 kb