Long-Term Effects of Experimental Carotid Stenosis on Hippocampal Infarct Pathology, Neurons and Glia and Amelioration by Environmental Enrichment

Hippocampal atrophy and pathology are common in ageing-related disorders and associated with cognitive impairment and dementia. We explored whether environmental enrichment (EE) ameliorated the pathological sequelae in the hippocampus subsequent to chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Seventy-four male C57BL/6 J mice underwent BCAS or sham surgery. One-week after surgery, mice were exposed to three different degrees of EE; either standard housing conditions (std), limited 3-hour exposure to EE per day (3h) or full-time exposure to EE (full) for 3 months. Four months after surgery, the hippocampus was examined for the extent of vascular brain injury and neuronal and glial changes. Results showed that long-term BCAS induced strokes, most often in CA1 subfield, reduced 40-50% CA1 neurons (P<0.01) and increased microglia/macrophage in CA1-CA3 subfields (P<0.02). Remarkably, both 3h and full-time EE regimes attenuated hippocampal neuronal death and repressed recurrent strokes with complete prevention of larger infarcts in mice on full-time EE (P<0.01). Full-time EE also reduced astrocytic clasmatodendrosis and microglial/macrophage activation in all CA subfields. Our results suggest that exposure to EE differentially reduces long-term hypoperfusive hippocampal damage. The implementation of even limited EE may be beneficial for patients diagnosed with vascular cognitive impairment

Guided, internet based, cognitive behavioural therapy for post-traumatic stress disorder: pragmatic, multicentre, randomised controlled non-inferiority trial (RAPID)

Objective To determine if guided internet based cognitive behavioural therapy with a trauma focus (CBT-TF) is non-inferior to individual face-to-face CBT-TF for mild to moderate post-traumatic stress disorder (PTSD) to one traumatic event. Design Pragmatic, multicentre, randomised controlled non-inferiority trial (RAPID). Setting Primary and secondary mental health settings across the UK’s NHS. Participants 196 adults with a primary diagnosis of mild to moderate PTSD were randomised in a 1:1 ratio to one of two interventions, with 82% retention at 16 weeks and 71% retention at 52 weeks. 19 participants and 10 therapists were purposively sampled and interviewed for evaluation of the process. Interventions Up to 12 face-to-face, manual based, individual CBT-TF sessions, each lasting 60-90 minutes; or guided internet based CBT-TF with an eight step online programme, with up to three hours of contact with a therapist and four brief telephone calls or email contacts between sessions. Main outcome measures Primary outcome was the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) at 16 weeks after randomisation (diagnosis of PTSD based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, DSM-5). Secondary outcomes included severity of PTSD symptoms at 52 weeks, and functioning, symptoms of depression and anxiety, use of alcohol, and perceived social support at 16 and 52 weeks after randomisation. Results Non-inferiority was found at the primary endpoint of 16 weeks on the CAPS-5 (mean difference 1.01, one sided 95% confidence interval −∞ to 3.90, non-inferiority P=0.012). Improvements in CAPS-5 score of more than 60% in the two groups were maintained at 52 weeks, but the non-inferiority results were inconclusive in favour of face-to-face CBT-TF at this time point (3.20, −∞ to 6.00, P=0.15). Guided internet based CBT-TF was significantly (P<0.001) cheaper than face-to-face CBT-TF and seemed to be acceptable and well tolerated by participants. The main themes of the qualitative analysis were facilitators and barriers to engagement with guided internet based CBT-TF, treatment outcomes, and considerations for its future implementation. Conclusions Guided internet based CBT-TF for mild to moderate PTSD to one traumatic event was non-inferior to individual face-to-face CBT-TF and should be considered a first line treatment for people with this condition

Tau Proteins in the Temporal and Frontal Cortices in Patients With Vascular Dementia

We previously reported that, in the brains of older patients with vascular dementia (VaD), there is a distinctive accumulation of detergent-extractable soluble amyloid-β, with a predominance of Aβ42 species. It is unclear, however, if tau proteins also accumulate in the brains of older VaD subjects. Using antibody-specific immunoassays, we assessed concentrations of total tau (t-tau) and phosphorylated tau protein, measured at 3 phosphorylated sites (i.e. Thr181, Ser202/Thr205, and Ser262), as well as synaptophysin in the temporal and frontal cortices of 18 VaD, 16 Alzheimer disease (AD), and 16 normal age-matched control subjects. There was selective loss of t-tau protein in VaD compared with controls and AD subjects (p < 0.021 and p < 0.001, respectively). In contrast, phosphorylated tau levels were similar to controls in VaD in both regions, but they were increased in the temporal lobes of patients with AD (p < 0.01 and p < 0.0001 for Ser202/Thr205 and Ser262 phosphorylated sites, respectively). The reduced t-tau in the VaD group was unrelated to any low-level neurofibrillary or amyloid pathology or age at death. These findings suggest that breaches of microvascular or microstructural tissue integrity subsequent to ischemic injury in older age may modify tau protein metabolism or phosphorylation and have effects on the burden of neurofibrillary pathology characteristic of AD

Primary Care implementation of Germ Defence, a digital behaviour change intervention to improve household infection control during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial

ObjectivesTo examine the effectiveness of randomising dissemination of the Germ Defence behaviour change website via GP practices across England UK.Trial designA two-arm (1:1 ratio) cluster randomised controlled trial implementing Germ Defence via GP practices compared with usual care.ParticipantsSetting: All Primary care GP practices in England. Participants: All patients aged 16 years and over who were granted access by participating GP practices.Intervention and comparatorIntervention: We will ask staff at GP practices randomised to the intervention arm to share the weblink to Germ Defence with all adult patients registered at their practice during the 4-month trial implementation period and care will otherwise follow current standard management. Germ Defence is an interactive website (http://GermDefence.org/) employing behaviour change techniques and practical advice on how to reduce the spread of infection in the home. The coronavirus version of Germ Defence helps people understand what measures to take and when to take them to avoid infection. This includes hand washing, avoiding sharing rooms and surfaces, dealing with deliveries and ventilating rooms. Using behaviour change techniques, it helps users think through and adopt better home hygiene habits and find ways to solve any barriers, providing personalised goal setting and tailored advice that fits users’ personal circumstances and problem solving to overcome barriers.Comparator: Patients at GP practices randomised to the usual care arm will receive current standard management for the 4-month trial period after which we will ask staff to share the link to Germ Defence with all adult patients registered at their practice.Main outcomesThe primary outcome is the effects of implementing Germ Defence on prevalence of all respiratory tract infection diagnoses during the 4-month trial implementation period.The secondary outcomes are:1) incidence of COVID-19 diagnoses2) incidence of COVID-19 symptom presentation3) incidence of gastrointestinal infections4) number of primary care consultations5) antibiotic usage6) hospital admissions7) uptake of GP practices disseminating Germ Defence to their patients8) usage of the Germ Defence website by individuals who were granted access by their GP practiceRandomisationGP practices will be randomised on a 1:1 basis by the independent Bristol Randomised Trials Collaboration (BRTC). Clinical Commission Groups (CCGs) in England will be divided into blocks according to region, and equal numbers in each block will be randomly allocated to intervention or usual care. The randomisation schedule will be generated in Stata statistical software by a statistician not otherwise involved in the enrolment of general practices into the study.Blinding (masking)The principal investigators, the statistician and study collaborators will remain blinded from the identity of randomised practices until the end of the study.Numbers to be randomised (sample size)To detect planned effect size (based on PRIMIT trial, Little et al, 2015): 11.1 million respondents from 6822 active GP practices. Assuming 25% of these GP practices will engage, we will contact all GP practices in England spread across 135 Clinical Commissioning Groups.Trial statusProtocol version 2.0, dated 13 January 2021. Implementation is ongoing. The implementation period started on 10 November 2020 and will end on 10 March 2021.Trial registrationThis trial was registered in the ISRCTN registry (isrctn.com/ISRCTN14602359) on 12 August 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol