Unified ethical principles and an animal research 'Helsinki' declaration as foundations for international collaboration.

Ethical frameworks are the foundation for any research with humans or nonhuman animals. Human research is guided by overarching international ethical principles, such as those defined in the Helsinki Declaration by the World Medical Association. However, for nonhuman animal research, because there are several sets of ethical principles and national frameworks, it is commonly thought that there is substantial variability in animal research approaches internationally and a lack of an animal research 'Helsinki Declaration', or the basis for one. We first overview several prominent sets of ethical principles, including the 3Rs, 3Ss, 3Vs, 4Fs and 6Ps. Then using the 3Rs principles, originally proposed by Russell & Burch, we critically assess them, asking if they can be Replaced, Reduced or Refined. We find that the 3Rs principles have survived several replacement challenges, and the different sets of principles (3Ss, 3Vs, 4Fs and 6Ps) are complementary, a natural refinement of the 3Rs and are ripe for integration into a unified set of principles, as proposed here. We also overview international frameworks and documents, many of which incorporate the 3Rs, including the Basel Declaration on animal research. Finally, we propose that the available animal research guidance documents across countries can be consolidated, to provide a similar structure as seen in the Helsinki Declaration, potentially as part of an amended Basel Declaration on animal research. In summary, we observe substantially greater agreement on and the possibility for unification of the sets of ethical principles and documents that can guide animal research internationally.

Stepping up from opt-out: Achieving 100% uptake antenatal human immunodeficiency virus testing.

All pregnant women in the United Kingdom are offered and encouraged to take up screening for human immunodeficiency virus (HIV), hepatitis B and syphilis, with excellent uptake rates and engagement in care resulting in very few infants being infected with HIV in the United Kingdom. However, in that small number of women who decline testing, there remains an opportunity to offer further support to test and engage them and their baby in care, even if this happens in labour or immediately after birth. In addition, these women may be at increased risk of HIV. Our hospital is in an extremely high prevalence area for HIV, and most untested individuals are of childbearing age. We embarked on a quality improvement project to engage all women delivering at our unit in HIV testing or to test their babies via cord blood at birth. We sought to do this in a constructive and inclusive way, led by the HIV specialist midwife with the support of the HIV antenatal and the hospital senior management teams. Following an initial evaluation, the approach was modified and an innovative approach together with a trusted advocate was used to engage a particularly hard-to-reach group. We have achieved 100% uptake of HIV testing and made two HIV diagnoses that would not otherwise have been made; both in women who reported themselves not to be at risk and both engaged in care and delivered HIV-negative infants.

A mixed methods study examining perceptions by service-users of their involuntary admission in relation to levels of insight.

BACKGROUND: Poor insight is associated with negative attitudes to involuntary admission and care in qualitative studies. AIMS: The current paper aims to examine and compare retrospective qualitative perceptions of service-users in relation to their involuntary admission with their levels of clinical insight, using a mixed methods approach. METHODS: Forty two participants were assessed 3 months after the revocation of their involuntary admission. Each provided qualitative data relating to their perceptions of the coercive care process, which was analysed using content analysis, along with a quantitative measurement of insight, the Schedule for the Assessment of Insight-Expanded (SAI-E). Employing a mixed methods design and incorporating NVivo matrix coding queries, the datasets were merged to enable qualitative themes to be identified against the quantitative data. RESULTS: Differences were observed between those with high and low insight in terms of their understanding of the need for treatment, their levels of arousal at the time of admission and how they perceived the compassion of health professionals. Certain negative perceptions of care appeared more universal and were common across those with high and low insight. CONCLUSION: Some negative perceptions of coercive practices appear linked to inherent elements of psychotic illness such as unawareness of illness. Individuals with higher levels of insight tended to perceive their involuntary admission and receiving a diagnosis as beneficial. Negative views that persist amongst service users with high insight levels can highlight areas for successful service improvement, including increased emphasis on non-pharmacotherapy based supports during the coercive care process.

Community-driven citizen science approach to explore cardiovascular disease risk perception, and develop prevention advocacy strategies in sub-Saharan Africa: a programme protocol.

BACKGROUND: In sub-Saharan Africa (SSA), which experiences a disproportionately high cardiovascular disease (CVD) burden, population-based screening and prevention measures are hampered by low levels of knowledge about CVD and associated risk factors, and inaccurate perceptions of severity of risk. METHODS: This protocol describes the planned processes for implementing community-driven participatory research, using a citizen science method to explore CVD risk perceptions and to develop community-specific advocacy and prevention strategies in the rural and urban SSA settings. Multi-disciplinary research teams in four selected African countries will engage with and train community members living in rural and urban communities as citizen scientists to facilitate conceptualization, co-designing of research, data gathering, and co-creation of knowledge that can lead to a shared agenda to support collaborative participation in community-engaged science. The emphasis is on robust community engagement, using mobile technology to support data gathering, participatory learning, and co-creation of knowledge and disease prevention advocacy. DISCUSSION: Contextual processes applied and lessons learned in specific settings will support redefining or disassembling boundaries in participatory science to foster effective implementation of sustainable prevention intervention programmes in Low- and Middle-income countries.

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

The feasibility of a Comprehensive Resilience-building psychosocial Intervention (CREST) for people with dementia in the community: protocol for a non-randomised feasibility study.

BACKGROUND: A dementia diagnosis can prevent people from participating in society, leading to a further decline in cognitive, social and physical health. However, it may be possible for people with dementia to continue to live meaningful lives and continue to participate actively in society if a supportive psychosocial environment exists. Resilience theory, which focuses on strengthening personal attributes and external assets in the face of serious challenges, may provide a scaffold on which an inclusive multifaceted psychosocial supportive environment can be built. This protocol paper describes a study to determine the feasibility of conducting a multifaceted complex resilience building psychosocial intervention for people with dementia and their caregivers living in the community. METHODS: This is a non-randomised feasibility study. Ten participants with dementia and their primary caregivers living in the community will be recruited and receive the CREST intervention. The intervention provides (a) a 7-week cognitive stimulation programme followed by an 8-week physical exercise programme for people with dementia and (b) a 6-week educational programme for caregivers. Members of the wider community will be invited to a dementia awareness programme and GP practices to a dementia training workshop. Trained professionals will deliver all intervention components. Outcomes will assess the feasibility and acceptability of all study processes. The feasibility and acceptability of a range of outcomes to be collected in a future definitive trial, including economic measurements, will also be explored. Finally, social marketing will be used to map a route toward stigma change in dementia for use in a subsequent trial. Quantitative feasibility outcome assessments will be completed at baseline and after completion of the 15-week intervention while qualitative data will be collected at recruitment, baseline, during and post-intervention delivery. CONCLUSION: This feasibility study will provide evidence regarding the feasibility and acceptability of a comprehensive multifaceted psychosocial intervention programme for people with dementia and their caregivers (CREST). The results will be used to inform the development and implementation of a subsequent RCT, should the findings support feasibility. TRIAL REGISTRATION: ISRCTN25294519 Retrospectively registered 07.10.2019.

The Perceptions of People with Dementia and Key Stakeholders Regarding the Use and Impact of the Social Robot MARIO.

People with dementia often experience loneliness and social isolation. This can result in increased cognitive decline which, in turn, has a negative impact on quality of life. This paper explores the use of the social robot, MARIO, with older people living with dementia as a way of addressing these issues. A descriptive qualitative study was conducted to explore the perceptions and experiences of the use and impact of MARIO. The research took place in the UK, Italy and Ireland. Semi-structured interviews were held in each location with people with dementia (n = 38), relatives/carers (n = 28), formal carers (n = 28) and managers (n = 13). The data was analyzed using qualitative content analysis. The findings revealed that despite challenges in relation to voice recognition and the practicalities of conducting research involving robots in real-life settings, most participants were positive about MARIO. Through the robot's user-led design and personalized applications, MARIO provided a point of interest, social activities, and cognitive engagement increased. However, some formal carers and managers voiced concern that robots might replace care staff.

Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia.

BACKGROUND: Dementia is a worldwide concern. Its global prevalence is increasing. At present, there is no medication licensed to prevent or delay the onset of dementia. Inflammation has been suggested as a key factor in dementia pathogenesis. Therefore, medications with anti-inflammatory properties could be beneficial for dementia prevention. OBJECTIVES: To evaluate the effectiveness and adverse effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) for the primary or secondary prevention of dementia. SEARCH METHODS: We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group up to 9 January 2020. ALOIS contains records of clinical trials identified from monthly searches of several major healthcare databases, trial registries and grey literature sources. We ran additional searches across MEDLINE (OvidSP), Embase (OvidSP) and six other databases to ensure that the searches were as comprehensive and up-to-date as possible. We also reviewed citations of reference lists of included studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing aspirin or other NSAIDs with placebo for the primary or secondary prevention of dementia. We included trials with cognitively healthy participants (primary prevention) or participants with mild cognitive impairment (MCI) or cognitive complaints (secondary prevention). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the strength of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included four RCTs with 23,187 participants. Because of the diversity of these trials, we did not combine data to give summary estimates, but presented a narrative description of the evidence. We identified one trial (19,114 participants) comparing low-dose aspirin (100 mg once daily) to placebo. Participants were aged 70 years or older with no history of dementia, cardiovascular disease or physical disability. Interim analysis indicated no significant treatment effect and the trial was terminated slightly early after a median of 4.7 years' follow-up. There was no evidence of a difference in incidence of dementia between aspirin and placebo groups (risk ratio (RR) 0.98, 95% CI 0.83 to 1.15; high-certainty evidence). Participants allocated aspirin had higher rates of major bleeding (RR 1.37, 95% CI 1.17 to 1.60, high-certainty evidence) and slightly higher mortality (RR 1.14, 95% CI 1.01 to 1.28; high-certainty evidence). There was no evidence of a difference in activities of daily living between groups (RR 0.84, 95% CI 0.70 to 1.02; high-certainty evidence). We identified three trials comparing non-aspirin NSAIDs to placebo. All three trials were terminated early due to adverse events associated with NSAIDs reported in other trials. One trial (2528 participants) investigated the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib (200 mg twice daily) and the non-selective NSAID naproxen (220 mg twice daily) for preventing dementia in cognitively healthy older adults with a family history of Alzheimer's disease (AD). Median follow-up was 734 days. Combining both NSAID treatment arms, there was no evidence of a difference in the incidence of AD between participants allocated NSAIDs and those allocated placebo (RR 1.91, 95% CI 0.89 to 4.10; moderate-certainty evidence). There was also no evidence of a difference in rates of myocardial infarction (RR 1.21, 95% CI 0.61 to 2.40), stroke (RR 1.82, 95% CI 0.76 to 4.37) or mortality (RR 1.37, 95% CI 0.78 to 2.43) between treatment groups (all moderate-certainty evidence). One trial (88 participants) assessed the effectiveness of celecoxib (200 mg or 400 mg daily) in delaying cognitive decline in participants aged 40 to 81 years with mild age-related memory loss but normal memory performance scores. Mean duration of follow-up was 17.6 months in the celecoxib group and 18.1 months in the placebo group. There was no evidence of a difference between groups in test scores in any of six cognitive domains. Participants allocated celecoxib experienced more gastrointestinal adverse events than those allocated placebo (RR 2.66, 95% CI 1.05 to 6.75; low-certainty evidence). One trial (1457 participants) assessed the effectiveness of the COX-2 inhibitor rofecoxib (25 mg once daily) in delaying or preventing a diagnosis of AD in participants with MCI. Median duration of study participation was 115 weeks in the rofecoxib group and 130 weeks in the placebo group. There was a higher incidence of AD in the rofecoxib than the placebo group (RR 1.32, 95% CI 1.01 to 1.72; moderate-certainty evidence). There was no evidence of a difference between groups in cardiovascular adverse events (RR 1.07, 95% CI 0.68 to 1.66; moderate-certainty evidence) or mortality (RR 1.62, 95% CI 0.85 to 3.05; moderate-certainty evidence). Participants allocated rofecoxib had more upper gastrointestinal adverse events (RR 3.53, 95% CI 1.17 to 10.68; moderate-certainty evidence). Reported annual mean difference scores showed no evidence of a difference between groups in activities of daily living (year 1: no data available; year 2: 0.0, 95% CI -0.1 to 0.2; year 3: 0.1, 95% CI -0.1 to 0.3; year 4: 0.1, 95% CI -0.1 to 0.4; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is no evidence to support the use of low-dose aspirin or other NSAIDs of any class (celecoxib, rofecoxib or naproxen) for the prevention of dementia, but there was evidence of harm. Although there were limitations in the available evidence, it seems unlikely that there is any need for further trials of low-dose aspirin for dementia prevention. If future studies of NSAIDs for dementia prevention are planned, they will need to be cognisant of the safety concerns arising from the existing studies.

MARIO Project: Validation and Evidence of Service Robots for Older People with Dementia.

BACKGROUND: In the EU funded MARIO project, specific technological tools are adopted for the people living with dementia (PLWD). In the final stage of the project, a validation of the MARIO companion robot was performed from August to October 2017. OBJECTIVE: The aims of the present study are: 1) to illustrate the key results and evidence obtained in the final evaluation phase of the project across the three different pilot sites; 2) to assess the engagement dimensions of the PLWD who interacted with the MARIO robot; and 3) to assess the acceptability and efficacy of the MARIO companion robot on clinical, cognitive, neuropsychiatric, affective and social aspects, resilience, quality of life in PLWD, and burden level of the caregivers. METHODS: 38 people (M = 14; F = 24) with Alzheimer's disease were screened for eligibility and all were included. The following tests were administered Pre and Post interactions with MARIO: Observational Measurement of Engagement (OME), Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Frontal Assessment Battery (FAB), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Multidimensional Scale of Perceived Social Support (MSPSS), 14-item Resilience Scale (RS-14), Quality of Life in Alzheimer's Disease (QOL-AD), Caregiver Burden Inventory (CBI), Tinetti Balance Assessment (TBA), and Comprehensive Geriatric Assessment (CGA) was carried out. RESULTS: In Post-MARIO interactions, significant improvements were observed in RS-14 (p = 0.020).Considering the age of the people, PLWD with 68-76 years perceived that they had major social support (MSPSS Total: p = 0.016) and friends to support them (MSPSS Fri: p = 0.014). Indeed, the younger people (55-67 years) were less depressed (CSDD: p = 0.033), and more resilient (RS-14: p = 0.003). The people aged 77-85 years perceived they had major family support (MSPSS Fam: p = 0.018). The participants were gender and education matched without any statistically significant difference. CONCLUSION: MARIO may be a useful tool in mitigating depression and loneliness, while enhancing social connectedness, resilience, and overall quality of life for people with dementia.

Predictors of involuntary patients' satisfaction with care: prospective study.

BACKGROUND: Involuntary admission can be traumatic and is associated with negative attitudes that persist after the episode of illness has abated. AIMS: We aimed to prospectively assess satisfaction with care at the points of involuntary admission and symptomatic recovery, and identify their sociodemographic, clinical and service experience predictors. METHOD: Levels of satisfaction with care, and clinical and sociodemographic variables were obtained from a representative cohort of 263 patients at the point of involuntary admission and from 155 of these patients 3 months after termination of the involuntary admission. Data were analysed with multiple linear regression modelling. RESULTS: Higher baseline awareness of illness (B = 0.19, P < 0.001) and older age (B = 0.05, P = 0.001) were associated with more satisfaction with care at baseline and follow-up. Transition to greater satisfaction with care was associated with improvements in awareness of illness (B = 0.13, P < 0.001) and in symptoms (B = 0.05, P = 0.02), as well as older age (B = 0.04, P = 0.01). Objective coercive experiences were not associated with variation in satisfaction with care. CONCLUSIONS: There is wide variation in satisfaction with coercive care. Greater satisfaction with care is positively associated with clinical variables such as increased awareness of illness. DECLARATION OF INTEREST: None.

Individuals' experiences of involuntary admissions and preserving control: qualitative study.

BACKGROUND: A theoretical model of individuals' experiences before, during and after involuntary admission has not yet been established. AIMS: To develop an understanding of individuals' experiences over the course of the involuntary admission process. METHOD: Fifty individuals were recruited through purposive and theoretical sampling and interviewed 3 months after their involuntary admission. Analyses were conducted using a Straussian grounded theory approach. RESULTS: The 'theory of preserving control' (ToPC) emerged from individuals' accounts of how they adapted to the experience of involuntary admission. The ToPC explains how individuals manage to reclaim control over their emotional, personal and social lives and consists of three categories: 'losing control', 'regaining control' and 'maintaining control', and a number of related subcategories. CONCLUSIONS: Involuntary admission triggers a multifaceted process of control preservation. Clinicians need to develop therapeutic approaches that enable individuals to regain and maintain control over the course of their involuntary admission. DECLARATION OF INTEREST: None.

Macro-connectomics and microstructure predict dynamic plasticity patterns in the non-human primate brain.

The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not.

Improved methods for MRI-compatible implants in nonhuman primates.

BACKGROUND: Neuroscientists commonly use permanently implanted headposts to stabilize the head of nonhuman primates (NHPs) during electrophysiology and functional magnetic resonance imaging (fMRI). Here, we present improved methodology for MRI-compatible implants without the use of acrylic for head stabilization in NHPs. NEW METHOD: MRI is used to obtain a 3D-reconstruction of NHP skulls, which are used to create customized implants by modeling intersections with the bone. Implants are manufactured from PEEK using computer numerical control machining and coated with hydroxyapatite to promote osseointegration. Surgically, implants are attached to the skull with ceramic screws, while the skin flap is pulled over the implant and closed subcutaneously. RESULTS: Quality of blood oxygen level dependent (BOLD) fMRI signal is improved in animals implanted with our method as compared to traditional acrylic implants. Additionally, implants are well-integrated with the skull, remain robust for more than a year and without granulation tissue around the skin margin. COMPARISON WITH EXISTING METHOD(S): Previous improvements on NHP implants (Chen et al., 2017; McAndrew et al., 2012; Mulliken et al., 2015; Overton et al., 2017) lacked fMRI-compatibility, as they relied on titanium headposts and/or titanium screws. Thus, most fMRI studies in NHPs today still rely on the use of acrylic-based headposts for stabilization and the use of contrast-enhanced agents to improve MRI signal. CONCLUSIONS: Our method preserves fMRI-compatibility and results in measurable improvement in BOLD signal without the use of contrast-enhanced agents. Furthermore, the long-term stability of our implants contributes positively to the wellbeing of NHPs in neuroscience research.

The Rhesus Monkey Hippocampus Critically Contributes to Scene Memory Retrieval, But Not New Learning.

Humans can recall a large number of memories years after the initial events. Patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. Rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to temporally graded or ungraded amnesia, which could be a consequence of differences between rodent and human studies. In the current study, rhesus monkeys of both sexes received either bilateral neurotoxic hippocampal lesions or remained unoperated controls and were tested on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but the role of the damaged hippocampus can be taken over by spared hippocampal tissue or extra-hippocampal regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.SIGNIFICANCE STATEMENT Recalling old memories, creating new memories, and the process by which memories transition from temporary to permanent storage all may rely on the hippocampus. Whether the hippocampus is necessary for encoding and retrieval of multiple related visual memories in primates is not known. Monkeys that learned many visual memory problems before precise lesions of the hippocampus were impaired at recalling those memories after hippocampal damage regardless of when the memories were formed, but could learn new memory problems at a normal rate. This suggests the hippocampus is normally vital for retrieval of complex visual memories regardless of their age, and also points to the importance of investigating mechanisms by which memories may be acquired in the presence of hippocampal damage.