A gut-derived metabolite alters brain activity and anxiety behaviour in mice.

Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

Synapse pathology in Alzheimer's disease.

Synapse loss and damage are central features of Alzheimer's disease (AD) and contribute to the onset and progression of its behavioural and physiological features. Here we review the literature describing synapse pathology in AD, from what we have learned from microscopy in terms of its impacts on synapse architecture, to the mechanistic role of Aß, tau and glial cells, mitochondrial dysfunction, and the link with AD risk genes. We consider the emerging view that synapse pathology may operate at a further level, that of synapse diversity, and discuss the prospects for leveraging new synaptome mapping methods to comprehensively understand the molecular properties of vulnerable and resilient synapses. Uncovering AD impacts on brain synapse diversity should inform therapeutic approaches targeted at preserving or replenishing lost and damaged synapses and aid the interpretation of clinical imaging approaches that aim to measure synapse damage.

Three-dimensional imaging for the quantification of spatial patterns in microbiota of the intestinal mucosa.

Improving our understanding of host­microbe relationships in the gut requires the ability to both visualize and quantify the spatial organization of microbial communities in their native orientation with the host tissue. We developed a systematic procedure to quantify the three-dimensional (3D) spatial structure of the native mucosal microbiota in any part of the intestines with taxonomic and high spatial resolution. We performed a 3D biogeographical analysis of the microbiota of mouse cecal crypts at different stages of antibiotic exposure. By tracking eubacteria and four dominant bacterial taxa, we found that the colonization of crypts by native bacteria is a dynamic and spatially organized process. Ciprofloxacin treatment drastically reduced bacterial loads and eliminated Muribaculaceae (or all Bacteroidetes entirely) even 10 d after recovery when overall bacterial loads returned to preantibiotic levels. Our 3D quantitative imaging approach revealed that the bacterial colonization of crypts is organized in a spatial pattern that consists of clusters of adjacent colonized crypts that are surrounded by unoccupied crypts, and that this spatial pattern is resistant to the elimination of Muribaculaceae or of all Bacteroidetes by ciprofloxacin. Our approach also revealed that the composition of cecal crypt communities is diverse and that Lactobacilli were found closer to the lumen than Bacteroidetes, Ruminococcaceae, and Lachnospiraceae, regardless of antibiotic exposure. Finally, we found that crypts communities with similar taxonomic composition were physically closer to each other than communities that were taxonomically different.

The effectiveness, implementation, and experiences of peer support approaches for mental health: a systematic umbrella review.

BACKGROUND: Peer support for mental health is recommended across international policy guidance and provision. Our systematic umbrella review summarises evidence on the effectiveness, implementation, and experiences of paid peer support approaches for mental health. METHODS: We searched MEDLINE, EMBASE, PsycINFO, The Campbell Collaboration, and The Cochrane Database of Systematic Reviews (2012-2022) for reviews of paid peer support interventions for mental health. The AMSTAR2 assessed quality. Results were synthesised narratively, with implementation reported using the CFIR (Consolidated Framework for Implementation Research). The protocol was registered with PROSPERO (registration number: CRD42022362099). RESULTS: We included 35 reviews (426 primary studies, n = 95-40,927 participants): systematic reviews with (n = 13) or without (n = 13) meta-analysis, or with qualitative synthesis (n = 3), scoping reviews (n = 6). Most reviews were low or critically low (97%) quality, one review was high quality. Effectiveness was investigated in 23 reviews. Results were mixed; there was some evidence from meta-analyses that peer support may improve depression symptoms (particularly perinatal depression), self-efficacy, and recovery. Factors promoting successful implementation, investigated in 9 reviews, included adequate training and supervision, a recovery-oriented workplace, strong leadership, and a supportive and trusting workplace culture with effective collaboration. Barriers included lack of time, resources and funding, and lack of recognised peer support worker (PSW) certification. Experiences of peer support were explored in 11 reviews, with 3 overarching themes: (i) what the PSW role can bring, including recovery and improved wellbeing for service users and PSWs; (ii) confusion over the PSW role, including role ambiguity and unclear boundaries; and (iii) organisational challenges and impact, including low pay, negative non-peer staff attitudes, and lack of support and training. CONCLUSIONS: Peer support may be effective at improving some clinical outcomes, self-efficacy, and recovery. Certain populations, e.g. perinatal populations, may especially benefit from peer support. Potential strategies to successfully implement PSWs include co-production, clearly defined PSW roles, a receptive hierarchical structure and staff, appropriate PSW and staff training with clinical and/or peer supervision alongside safeguarding. Services could benefit from clear, coproduced, setting specific implementation guidelines for PSW. PSW roles tend to be poorly defined and associations between PSW intervention content and impacts need further investigation. Future research should reflect the priorities of providers/service users involved in peer support.

Approaches to improving mental health care for autistic children and young people: a systematic review and meta-analysis.

Autistic children and young people (CYP) experience mental health difficulties but face many barriers to accessing and benefiting from mental health care. There is a need to explore strategies in mental health care for autistic CYP to guide clinical practice and future research and support their mental health needs. Our aim was to identify strategies used to improve mental health care for autistic CYP and examine evidence on their acceptability, feasibility, and effectiveness. A systematic review and meta-analysis were carried out. All study designs reporting acceptability/feasibility outcomes and empirical quantitative studies reporting effectiveness outcomes for strategies tested within mental health care were eligible. We conducted a narrative synthesis and separate meta-analyses by informant (self, parent, and clinician). Fifty-seven papers were included, with most investigating cognitive behavioral therapy (CBT)-based interventions for anxiety and several exploring service-level strategies, such as autism screening tools, clinician training, and adaptations regarding organization of services. Most papers described caregiver involvement in therapy and reported adaptations to communication and intervention content; a few reported environmental adjustments. In the meta-analyses, parent- and clinician-reported outcomes, but not self-reported outcomes, showed with moderate certainty that CBT for anxiety was an effective treatment compared to any comparison condition in reducing anxiety symptoms in autistic individuals. The certainty of evidence for effectiveness, synthesized narratively, ranged from low to moderate. Evidence for feasibility and acceptability tended to be positive. Many identified strategies are simple, reasonable adjustments that can be implemented in services to enhance mental health care for autistic individuals. Notable research gaps persist, however.

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.

In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-ß (Aß) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of Aß-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

A scoping review of trauma informed approaches in acute, crisis, emergency, and residential mental health care.

Experiences of trauma in childhood and adulthood are highly prevalent among service users accessing acute, crisis, emergency, and residential mental health services. These settings, and restraint and seclusion practices used, can be extremely traumatic, leading to a growing awareness for the need for trauma informed care (TIC). The aim of TIC is to acknowledge the prevalence and impact of trauma and create a safe environment to prevent re-traumatisation. This scoping review maps the TIC approaches delivered in these settings and reports related service user and staff experiences and attitudes, staff wellbeing, and service use outcomes.We searched seven databases (EMBASE; PsycINFO; MEDLINE; Web of Science; Social Policy and Practice; Maternity and Infant Care Database; Cochrane Library Trials Register) between 24/02/2022-10/03/2022, used backwards and forwards citation tracking, and consulted academic and lived experience experts, identifying 4244 potentially relevant studies. Thirty-one studies were included.Most studies (n = 23) were conducted in the USA and were based in acute mental health services (n = 16). We identified few trials, limiting inferences that can be drawn from the findings. The Six Core Strategies (n = 7) and the Sanctuary Model (n = 6) were the most commonly reported approaches. Rates of restraint and seclusion reportedly decreased. Some service users reported feeling trusted and cared for, while staff reported feeling empathy for service users and having a greater understanding of trauma. Staff reported needing training to deliver TIC effectively.TIC principles should be at the core of all mental health service delivery. Implementing TIC approaches may integrate best practice into mental health care, although significant time and financial resources are required to implement organisational change at scale. Most evidence is preliminary in nature, and confined to acute and residential services, with little evidence on community crisis or emergency services. Clinical and research developments should prioritise lived experience expertise in addressing these gaps.

A mixed-methods feasibility study of a goal-focused manualised intervention to support people with dementia to stay living independently at home with support from family carers: NIDUS (New Interventions for Independence in Dementia Study) Family.

OBJECTIVES: To examine the feasibility and acceptability of NIDUS-Family, a 6-8 session manualised, individually tailored, modular intervention supporting independence at home for people with dementia; and explore participants' and facilitators' experiences of the intervention. METHOD: In this single group multi-site feasibility study, trained, supervised non-clinically qualified graduates (facilitators) delivered NIDUS-Family to family carer and people living with dementia dyads. We recruited participants from GP practices and memory services in London and Bradford. We completed quantitative outcomes pre- and post-intervention; and conducted qualitative interviews with participants and facilitators. Our pre-specified main outcomes were proportion of potential participants approached who agreed to participate, intervention adherence and acceptability to family carers, and facilitator fidelity to the manual. RESULTS: We recruited 16 dyads (57% of those approached); 12 (75%) completed the intervention. Of 12 participants rating intervention acceptability, 9 (75%) agreed or strongly agreed that it had helped; 2 (18%) neither agreed nor disagreed and 1 (8%) disagreed. Mean facilitator fidelity was high (81.5%). Dyads set on average 3.9 goals; these most commonly related to getting out and about and increasing activity/hobby participation (n = 10); carer wellbeing (n = 6), managing physical complaints (n = 6); meal preparation/cooking (n = 5); and reducing irritability, frustration or aggression (n = 5). Almost all secondary outcomes changed in a direction indicating improvement. In our qualitative analysis we identified three overarching themes; relationships facilitate change, goal-focused versus manualised approach and balancing the needs of carers and people with dementia. CONCLUSION: NIDUS-Family was feasible and acceptable to participants. Following refinements, testing in a pragmatic trial is underway.

A qualitative comparison of experiences of specialist mother and baby units versus general psychiatric wards.

BACKGROUND: Mother and baby units (MBUs) are an inpatient mental health service where women experiencing acute severe postpartum psychiatric difficulties can be admitted with their babies. They are currently viewed as best practice in the UK and elsewhere. However, as service provision is fragmented, some women residing in areas without MBUs are admitted to acute general psychiatric wards without their infants. This study aimed to compare qualitatively experiences of these two service types from the perspectives of women and clinicians. METHODS: Semi-structured interviews were conducted with fifteen women who received treatment for perinatal mental health problems on a general psychiatric ward and/or MBU in England. Two focus groups were also conducted, one with MBU staff (n = 11) and one with acute ward staff (n = 6). Data were analysed thematically. RESULTS: Women generally preferred being co-admitted with their baby to an MBU over lone admission to a general psychiatric ward. Women and clinicians felt that MBUs provided more perinatally-focused, family-centred care, and were better-equipped to meet women's needs. General wards were reported by women and staff to lack the necessary facilities and expertise to support perinatal women adequately, while separation of mothers and babies was often experienced by women as traumatic and detrimental to recovery. However, some areas for improvement were also identified across both service types, particularly relating to difficulties transitioning home post-discharge, inadequate support for family members, staffing issues and access problems (with MBUs). CONCLUSIONS: Findings suggest that specialist perinatal inpatient care is considered preferable to generic care in the perinatal period from both service user and staff perspectives. Increased collaboration between perinatal and non-perinatal services could help improve perinatal expertise on general psychiatric wards, while further expansion of perinatal services (e.g. to cater for women currently considered too high risk for MBUs and for those discharged from inpatient settings) could tackle other shortfalls in care.

Quantifying the carbon footprint of clinical trials: guidance development and case studies.

BACKGROUND: The urgency of the climate crisis requires attention from biomedical research, not least clinical trials which can involve significant greenhouse gas emissions. The Low Carbon Clinical Trials Working Group set out a strategy to reduce the emissions of clinical trials, starting with the development of a method to measure their carbon footprint (CO2e). METHODS: As a first step, we developed a process map defining clinical trial core activities. Corresponding emission factors were sourced to convert activity data into greenhouse gas emissions. The subsequent method was applied to two Cancer Research UK (CRUK)-funded trials (the international randomised sarcoma trial CASPS (ISRCTN63733470) and the UK cohort-based breast cancer trial PRIMETIME (ISRCTN41579286)). A guidance document defining the scope, method and assumptions was written to allow application to any publicly funded/investigator initiated clinical trial. RESULTS: Trial specific activities over and above routine care were grouped into 10 modules covering trial set up, conduct and closure. We identified emission factors for all trial activities within both trials and used them to estimate their total carbon footprint. The carbon footprint of CASPS, an international phase 2 trial of an investigational medicinal product with 47 participants, was 72 tonnes CO2e, largely attributable to clinical trials unit emissions and staff travel. PRIMETIME, a UK-based phase 3 non-investigational medicinal product trial with 1962 patients, produced 89 tonnes CO2e, largely attributable to trial-specific in-person participant assessments. CONCLUSION: We have developed a method and guidance that trialists can use to determine the carbon footprint of clinical trials. The guidance can be used to identify carbon hotspots where alternative approaches to trial design and conduct could reduce a trial footprint, and where methodology research is required to investigate the potential impact of interventions taken to reduce carbon emissions. We will continue to refine the guidance to increase the potential application and improve usability.