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The causes that trigger the onset of dementia are still unknown. Recently there has been an increasing interest in the possible role of infectious agents in the brain in the pathogenesis of this condition. Amongst the viruses, members of the Herpesviridae family, namely herpes simplex virus-1 (HSV1), cytomegalovirus (CMV), human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7) and varicella zoster virus (VZV) have been suggested as potential causes of the disease. However, the relative importance of these and other viruses in contributing to dementia remains unclear. We evaluated the association between seropositivity status of all viruses available in a large, population-based dataset (the UK Biobank) and dementia risk in an unbiased way. Of the 15 viruses investigated, our results showed a statistically significant increase of dementia risk associated only with HSV1 seropositivity (OR 2.14, 95% C.I. 1.21-3.81). However, by combining the data we found that seropositivity for 4 viruses (HSV1, HHV6, HHV7 and VZV) also significantly increases the risk of dementia (OR = 2.37, 95% C.I. 1.43-3.92). These four viruses have been described previously as neurotropic viruses. Our results provide support for a role for neurotropic viruses in the pathology of dementia., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To investigate the association between shingles and dementia, and between Zostavax vaccination and dementia., Design: Nested case-control study., Settings: Data were drawn from the UK Biobank cohort study with a total of 228 223 participants with Hospital Episodes Statistics and primary care linkage health records., Participants: The analyses included 2378 incident dementia cases and 225 845 controls. Inclusion criteria for incident cases were a dementia diagnosis 3 years or more after the first assessment date derived from all sources including International Classification of Diseases (ICD)-10, ICD-9, self-report and primary care linkage records. Subjects with no dementia code from all sources were coded as controls. Both shingles and Zostavax vaccination were investigated for their association with dementia risk., Results: There was a small but non-significant increase in the risk of dementia in subjects with shingles diagnosed 3 years or more prior to dementia diagnosis (OR: 1.088 with 95% CI: 0.978 to 1.211). In those subjects who had had Zostavax vaccination, the risk of dementia significantly decreased (OR: 0.808 with 95% CI: 0.657 to 0.993)., Conclusion: A history of shingles was not associated with an increased risk of dementia. In subjects who were eligible for the immunisation and vaccinated with Zostavax, we saw reduced risk of developing dementia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is limited evidence about the effectiveness of rehabilitation in meeting the longer-term needs of stroke patients and their carers., Objective: To determine the clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS)., Design: A pragmatic, observer-blind, parallel-group, multicentre randomised controlled trial with embedded health economic and process evaluations. Participants were randomised (1 : 1) to receive EXTRAS or usual care., Setting: Nineteen NHS study centres., Participants: Patients with a new stroke who received early supported discharge and their informal carers., Interventions: Five EXTRAS reviews provided by an early supported discharge team member between 1 and 18 months post early supported discharge, usually over the telephone. Reviewers assessed rehabilitation needs, with goal-setting and action-planning. Control treatment was usual care post early supported discharge., Main Outcome Measures: The primary outcome was performance in extended activities of daily living (Nottingham Extended Activities of Daily Living Scale) at 24 months post randomisation. Secondary outcomes at 12 and 24 months included patient mood (Hospital Anxiety and Depression Scale), health status (Oxford Handicap Scale), experience of services and adverse events. For carers, secondary outcomes included carers' strain (Caregiver Strain Index) and experience of services. Cost-effectiveness was estimated using resource utilisation costs (adaptation of the Client Service Receipt Inventory) and quality-adjusted life-years., Results: A total of 573 patients (EXTRAS, n  = 285; usual care, n  = 288) with 194 carers (EXTRAS, n  = 103; usual care, n  = 91) were randomised. Mean 24-month Nottingham Extended Activities of Daily Living Scale scores were 40.0 (standard deviation 18.1) for EXTRAS ( n  = 219) and 37.2 (standard deviation 18.5) for usual care ( n  = 231), giving an adjusted mean difference of 1.8 (95% confidence interval -0.7 to 4.2). The mean intervention group Hospital Anxiety and Depression Scale scores were not significantly different at 12 and 24 months. The intervention did not improve patient health status or carer strain. EXTRAS patients and carers reported greater satisfaction with some aspects of care. The mean cost of resource utilisation was lower in the intervention group: -£311 (95% confidence interval -£3292 to £2787), with a 68% chance of EXTRAS being cost-saving. EXTRAS was associated with 0.07 (95% confidence interval 0.01 to 0.12) additional quality-adjusted life-years. At current conventional thresholds of willingness to pay for a quality-adjusted life-year, there is a 90% chance that EXTRAS is cost-effective., Conclusions: EXTRAS did not improve stroke survivors' performance in extended activities of daily living but did improve their overall satisfaction with services. Given the impact on costs and quality-adjusted life-years, there is a high chance that EXTRAS could be considered cost-effective., Future Work: Further research is required to identify whether or not community-based interventions can improve performance of extended activities of daily living, and to understand the improvements in health-related quality of life and costs seen by provision of intermittent longer-term specialist review., Trial Registration: Current Controlled Trials ISRCTN45203373., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 24. See the NIHR Journals Library website for further project information., Competing Interests: Gary A Ford declares personal fees from AstraZeneca (Cambridge, UK), Bayer AG (Leverkusen, Germany), Medtronic (Dublin, Ireland), Pfizer (New York, NY, USA), Pulse Therapeutics Euphrates Vascular (St Louis, MO, USA), Stryker Corporation (Kalamazoo, MI, USA) and Amgen (Thousand Oaks, CA, USA), and grants from Daiichi Sankyo (Tokyo, Japan), Medtronic and Pfizer outside the submitted work. Anne Forster declares grants from the National Institute for Health Research (NIHR) and The Stroke Association (London, UK) outside the submitted work. She reports membership of the Health Services and Delivery Research (HSDR) Researcher-led Prioritisation Committee. Denise Howel was a member of the NIHR Programme Grants for Applied Research panel (2016 to present) and NIHR HSDR Commissioning Board (2012–15) during this research project. Luke Vale was a member the NIHR Health Technology Assessment (HTA) Clinical Evaluation and Trials panel (2014–18) during this research project. Helen Rodgers declares fees from Bayer and that during this research project she was a member of the British Association of Stroke Physicians (president) (2014–17), NIHR HTA Clinical Evaluation and Trials Board (2010–14), Intercollegiate Stroke Working Party (2002 to present), National Stroke Programme (chairperson of rehabilitation and ongoing care working group) (2018 to present) Joint Stroke Medicine Committee Royal College of Physicians London (chairperson) (2018 to present) and Steering Group member VISTA (Virtual International Stroke Trials Archive) (2015 to present).

Background and Purpose- There is limited evidence to guide rehabilitation to meet the longer term needs of stroke survivors. The clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS) provided following early supported discharge were determined. Methods- EXTRAS was a pragmatic parallel-group observer-blind randomized controlled trial involving 19 UK centers. Patients with stroke were individually randomized to receive EXTRAS or usual care at discharge from early supported discharge. Five EXTRAS reviews were provided by an early supported discharge team member between one and 18 months, usually by telephone. Reviews consisted of a semi-structured interview assessing progress, rehabilitation needs, and service provision, with goal setting and action planning. The primary outcome was performance in extended activities of daily living (Nottingham EADL Scale) at 24 months post-randomization. The Nottingham EADL Scale is scored 0 to 66, with higher scores indicating better performance in these activities. Cost-effectiveness was estimated using resource utilization costs and Quality Adjusted Life Years. Analyses were intention to treat. Results- Between January 9, 2013 and October 26, 2015, 573 participants were randomized (EXTRAS, n=285; usual care, n=288). Mean 24 month Nottingham EADL Scale scores were EXTRAS (n=219) 40.0 (SD 18.1) and usual care (n=231) 37.2 (SD 18.5) giving an adjusted mean difference of 1.8 (95% CI, -0.7 to 4.2). 1155/1338 (86%) of expected EXTRAS reviews were undertaken. Over 24 months, the mean cost of resource utilization was lower in the intervention group: -£311 (-$450 [95% CI, -£3292 to £2787; -$4764 to $4033]). EXTRAS provided more Quality Adjusted Life Years (0.07 [95% CI, 0.01 to 0.12]). At current conventional thresholds of willingness to pay (£20 000 [$28 940] per Quality Adjusted Life Years), there was a 90% chance that EXTRAS could be considered cost-effective. Conclusions- EXTRAS did not significantly improve stroke survivors' performance in extended activities of daily living. However, given the impact on costs and Quality Adjusted Life Years, EXTRAS may be an affordable addition to improve stroke care. Clinical Trial Registration- URL: www.isrctn.com. Unique identifier: ISRCTN45203373.