Muss Rewind Therapy to alleviate symptoms related to some form of traumatic experience: A thematic analysis of participants' experiences and their perceived effectiveness of MRT

Sometimes referred to as a memory reconsolidation treatment, Muss Rewind Therapy (MRT) is a brief psychological intervention which has shown promise in treating symptoms related to some forms of traumatic experience. This study aimed at adding to minimal existing research by exploring the experiences of UK participants who have chosen to self‐refer for MRT for help with symptoms they attributed to some form of previous traumatic experience. Ten participants were interviewed online, and qualitative data were collected using video recordings and transcription. A semistructured framework was employed to explore participants' individual experiences of MRT. All participants rated MRT as helping alleviate the symptoms they related to a previous traumatic experience. Several key themes emerged regarding the participants' experiences of the treatment, including the overall role of the therapist; participants being at the end of their tether before seeking help; experiencing negative emotions during the intervention; repetition of the MRT process in the therapy room; and experiencing some positive outcomes. However, it was unclear whether positive impacts reported after MRT were due specifically to MRT or nonspecific therapy factors because of variations in the way the MRT protocol was delivered and inclusion of other techniques in or before the MRT sessions. Whilst more rigorous research is needed, including research which follows a strict protocol when MRT is provided, to compare MRT versus control group, this novel addition to the existing research, which looks at clients' perspectives on their experiences and their perceived effectiveness of MRT, can add to and inform further research development

An electronic clinical decision support system for the assessment and management of suicidality in primary care

Background: Suicide is a global public health concern, but it is preventable. Increased contact with primary care before the suicide or attempted suicide raises opportunities for intervention and prevention. However, suicide assessment and management is an area that many General Practitioners (GPs) find particularly challenging. Previous research has indicated significant variability in how GPs understand, operationalise and assess suicide risk which subsequently has an impact on clinical decision making. Clinical Decision Support systems (CDSS) have been widely implemented across different healthcare settings, including primary care to support practitioners in clinical decision making. CDSS may reduce inconsistencies in the identification, assessment and management of suicide risk by GPs by guiding them through the consultation and generating a risk assessment plan that can be shared with a service user or with specialised mental health services. Objective: To co-develop and test with end users (e.g. GPs, primary care attendees, mental health professionals) an e-CDSS to support GPs in the identification, assessment and management of suicidality in primary care. Methods: An ongoing embedded mixed methods study with four phases: 1) Qualitative interviews with GPs to explore their views on the content, format and use of the e-CDSS; consultation with two service user advisory groups (people aged ≤ 25 and people aged ≥25) to inform the content of the e-CDSS including phrasing of items and clarity; 2) Participatory co-production workshops with GPs, service users and clinical experts in suicidality to determine the content and format of the e-CDDS; gain consensus of the relevance of items; establish content validity (CVI) and identify pathways to implementation, using the Consolidated Framework for Implementation Research; 3) Building the e-CDSS so that it guides the GP through a consultation and 4) Usability testing of the e-CDSS with GPs and service users in one primary care practice involving a non-live and a live stage. Conclusions: This study will be the first to explore the feasibility, acceptability and usability of electronic guided decision support system for use in primary care consultations for the improved assessment and management of suicidality

Synaptic expression of TAR-DNA-binding protein 43 in the mouse spinal cord determined using super-resolution microscopy

Funding: This work was supported by Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), Chief Scientist Office, RS Macdonald Charitable Trust, ALS CURE Project, the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (695568 SYNNOVATE), Simons Foundation Autism Research Initiative (529085), and the Wellcome Trust (Technology Development grant 202932).Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may be associated with TAR-DNA-Binding Protein 43 (TDP-43) pathology. Cellular inclusions of hyperphosphorylated TDP-43 (pTDP-43) are a key hallmark of neurodegenerative diseases such ALS. However, there has been little characterisation of the synaptic expression of TDP-43 inside subpopulations of spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of pTDP-43 in populations of excitatory synapses near where motor neurons reside in the lateral ventral horn of the mouse lumbar spinal cord. We observe that TDP-43 is expressed in approximately half of spinal cord synapses as nanoscale clusters. Synaptic TDP-43 clusters are found most abundantly at synapses associated with VGLUT1-positive presynaptic terminals, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1G93a, compared to healthy controls, despite prominent structural deficits in VGLUT1-associated synapses in SOD1G93a mice. This research characterizes the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases.Publisher PDFPeer reviewe

Synaptic expression of TAR-DNA-binding protein 43 in the mouse spinal cord determined using super-resolution microscopy

Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may be associated with TAR-DNA-Binding Protein 43 (TDP-43) pathology. Cellular inclusions of hyperphosphorylated TDP-43 (pTDP-43) are a key hallmark of neurodegenerative diseases such ALS. However, there has been little characterisation of the synaptic expression of TDP-43 inside subpopulations of spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of pTDP-43 in populations of excitatory synapses near where motor neurons reside in the lateral ventral horn of the mouse lumbar spinal cord. We observe that TDP-43 is expressed in approximately half of spinal cord synapses as nanoscale clusters. Synaptic TDP-43 clusters are found most abundantly at synapses associated with VGLUT1-positive presynaptic terminals, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1G93a, compared to healthy controls, despite prominent structural deficits in VGLUT1-associated synapses in SOD1G93a mice. This research characterises the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases

PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits

The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.Support from the Wellcome Trust, Medical Research Council, European Commission.This is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep2462

PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits.

The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.Support from the Wellcome Trust, Medical Research Council, European Commission.This is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep2462

Mechanisms of Hearing Loss after Blast Injury to the Ear

Given the frequent use of improvised explosive devices (IEDs) around the world, the study of traumatic blast injuries is of increasing interest. The ear is the most common organ affected by blast injury because it is the bodyﾒs most sensitive pressure transducer. We fabricated a blast chamber to re-create blast profiles similar to that of IEDs and used it to develop a reproducible mouse model to study blast-induced hearing loss. The tympanic membrane was perforated in all mice after blast exposure and found to heal spontaneously. Micro-computed tomography demonstrated no evidence for middle ear or otic capsule injuries; however, the healed tympanic membrane was thickened. Auditory brainstem response and distortion product otoacoustic emission threshold shifts were found to be correlated with blast intensity. As well, these threshold shifts were larger than those found in control mice that underwent surgical perforation of their tympanic membranes, indicating cochlear trauma. Histological studies one week and three months after the blast demonstrated no disruption or damage to the intra-cochlear membranes. However, there was loss of outer hair cells (OHCs) within the basal turn of the cochlea and decreased spiral ganglion neurons (SGNs) and afferent nerve synapses. Using our mouse model that recapitulates human IED exposure, our results identify that the mechanisms underlying blast-induced hearing loss does not include gross membranous rupture as is commonly believed. Instead, there is both OHC and SGN loss that produce auditory dysfunction

The development of an electronic clinical decision support system to assist with the identification, assessment and management of suicidality in primary care

Background: Primary care, is usually the first and last healthcare contact recorded by people who die by suicide. It previously been suggested that primary care holds potential to make a significant contribution to enhancing suicide and self-harm prevention. However, previous research highlights significant variability in the way GPs conceptualise, assess and manage patient suicidality, and previous attempts to offer GPs suicidality prevention training have generated inconclusive results. Previous research has identified a range of organisational and contextual factors negatively impacting on GPs ability to support patients in suicidality distress. As a result of these contextual considerations, GPs have previously suggested a clinical decision-making tool could support them in working with patient suicidality. Clinical decision support systems (CDSS) have been widely implemented in primary care for a range of ambulatory presentations, however no empirically evaluated CDSS exists to support GPs in working with patient suicidality. A CDSS could support GPs by guiding the consultation, supporting GPs’ clinical decision-making and standardising the way the consultation is recorded in patient’s clinical records. Methods: A mixed methods approach was adopted to develop the content of the CDSS and provide an initial evaluation of the prototype. The CDSS was developed following four empirical studies within the thesis. The first two studies gained perspectives of GPs through one-to-one interviews, and patients with experience of consulting a GP in relation to suicidality, through embedded consultation groups. The third empirical study brought together patients, GPs and suicide prevention experts to participate in a modified Delphi and expert consensus workshops to agree and shape the CDSS content. The fourth empirical study provided an initial usability evaluation of the prototype CDSS. Findings: Results of the studies corroborated known variation in the way GPs understand and conceptualise suicidality, and highlighted a range of contextual, organisational, and socio-cultural mechanisms which could influence GPs use of the CDSS. The studies shaped the content of the CDSS so that it was appropriate for the clinical and contextual demands of primary care practice. GPs reported the prototype CDSS possessed adequate usability and was acceptable in terms of its ease of use, content and ability to support their clinical decision-making. Conclusions: This research shows that the prototype CDSS has potential to improve GPs’ assessment and clinical management of patient suicidality in primary care. As an evidence-based quality improvement the CDSS could support GPs, and patients, to collaboratively discuss and care-plan in relation to suicidality and make an important contribution to promoting shared decision-making whilst enhancing suicide prevention efforts in primary care

The development of an electronic clinical decision support system to assist with the identification, assessment and management of suicidality in primary care

Background: Primary care, is usually the first and last healthcare contact recorded by people who die by suicide. It previously been suggested that primary care holds potential to make a significant contribution to enhancing suicide and self-harm prevention. However, previous research highlights significant variability in the way GPs conceptualise, assess and manage patient suicidality, and previous attempts to offer GPs suicidality prevention training have generated inconclusive results. Previous research has identified a range of organisational and contextual factors negatively impacting on GPs ability to support patients in suicidality distress. As a result of these contextual considerations, GPs have previously suggested a clinical decision-making tool could support them in working with patient suicidality. Clinical decision support systems (CDSS) have been widely implemented in primary care for a range of ambulatory presentations, however no empirically evaluated CDSS exists to support GPs in working with patient suicidality. A CDSS could support GPs by guiding the consultation, supporting GPs’ clinical decision-making and standardising the way the consultation is recorded in patient’s clinical records. Methods: A mixed methods approach was adopted to develop the content of the CDSS and provide an initial evaluation of the prototype. The CDSS was developed following four empirical studies within the thesis. The first two studies gained perspectives of GPs through one-to-one interviews, and patients with experience of consulting a GP in relation to suicidality, through embedded consultation groups. The third empirical study brought together patients, GPs and suicide prevention experts to participate in a modified Delphi and expert consensus workshops to agree and shape the CDSS content. The fourth empirical study provided an initial usability evaluation of the prototype CDSS. Findings: Results of the studies corroborated known variation in the way GPs understand and conceptualise suicidality, and highlighted a range of contextual, organisational, and socio-cultural mechanisms which could influence GPs use of the CDSS. The studies shaped the content of the CDSS so that it was appropriate for the clinical and contextual demands of primary care practice. GPs reported the prototype CDSS possessed adequate usability and was acceptable in terms of its ease of use, content and ability to support their clinical decision-making. Conclusions: This research shows that the prototype CDSS has potential to improve GPs’ assessment and clinical management of patient suicidality in primary care. As an evidence-based quality improvement the CDSS could support GPs, and patients, to collaboratively discuss and care-plan in relation to suicidality and make an important contribution to promoting shared decision-making whilst enhancing suicide prevention efforts in primary care