FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.

FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention.

The evolution of synaptic and cognitive capacity: Insights from the nervous system transcriptome of Aplysia.

The gastropod mollusk Aplysia is an important model for cellular and molecular neurobiological studies, particularly for investigations of molecular mechanisms of learning and memory. We developed an optimized assembly pipeline to generate an improved Aplysia nervous system transcriptome. This improved transcriptome enabled us to explore the evolution of cognitive capacity at the molecular level. Were there evolutionary expansions of neuronal genes between this relatively simple gastropod Aplysia (20,000 neurons) and Octopus (500 million neurons), the invertebrate with the most elaborate neuronal circuitry and greatest behavioral complexity? Are the tremendous advances in cognitive power in vertebrates explained by expansion of the synaptic proteome that resulted from multiple rounds of whole genome duplication in this clade? Overall, the complement of genes linked to neuronal function is similar between Octopus and Aplysia. As expected, a number of synaptic scaffold proteins have more isoforms in humans than in Aplysia or Octopus. However, several scaffold families present in mollusks and other protostomes are absent in vertebrates, including the Fifes, Lev10s, SOLs, and a NETO family. Thus, whereas vertebrates have more scaffold isoforms from select families, invertebrates have additional scaffold protein families not found in vertebrates. This analysis provides insights into the evolution of the synaptic proteome. Both synaptic proteins and synaptic plasticity evolved gradually, yet the last deuterostome-protostome common ancestor already possessed an elaborate suite of genes associated with synaptic function, and critical for synaptic plasticity.

A collaboratively produced model of service design for children and young people with common mental health problems.

BACKGROUND: Little is known about the effectiveness of, and implementation complexities associated with, service delivery models for children and young people (CYP) experiencing 'common' mental health problems such as anxiety, depression, behavioural difficulties and self-harm. This paper outlines how a model for high-quality service design for this population group was developed by identifying available services, their effectiveness, cost-effectiveness and acceptability, and the barriers and enablers to access. METHODS: Sequential, mixed-methods design, combining evidence syntheses (scoping and integrative reviews of the international literature) with primary research (a collective case study in England and Wales). Data from these two elements were collaboratively synthesised in a subsequent model-building phase. RESULTS: The scoping review yielded a service model typology. The integrative review found effectiveness evidence only for four models: collaborative care (the only service model to also have cost-effectiveness evidence), outreach approaches, brief intervention services and an organisational framework called 'Availability, Responsiveness and Continuity'. No service model seemed more acceptable than others. Three case study themes were identified: pathways to support; service engagement; and learning and understanding. The model-building phase identified rapid access, learning self-care skills, individualised support, clear information, compassionate and competent staff and aftercare planning as core characteristics of high-quality services. These characteristics were underpinned by four organisational qualities: values that respect confidentiality; engagement and involvement; collaborative relationships; and a learning culture. CONCLUSIONS: A consistent organisational evidence-base for service design and delivery in CYP's mental health spanning many years appears to have had little impact on service provision in England and Wales. Rather than impose - often inflexible and untested - specific local or national models or frameworks, those commissioning, designing and delivering mental health services for CYP should (re)focus on already known, fundamental components necessary for high-quality services. These fundamental components have been integrated into a collaboratively produced general model of service design for CYP with common mental health problems. While this general model is primarily focused on British service provision, it is broad enough to have utility for international audiences.

Genomic Confirmation of Borrelia garinii, United States.

Lyme disease is a multisystem disorder primarily caused by Borrelia burgdorferi sensu lato. However, B. garinii, which has been identified on islands off the coast of Newfoundland and Labrador, Canada, is a cause of Lyme disease in Eurasia. We report isolation and whole-genome nucleotide sequencing of a B. garinii isolate from a cotton mouse (Peromyscus gossypinus) in South Carolina, USA. We identified a second B. garinii isolate from the same repository. Phylogenetic analysis does not associate these isolates with the previously described isolates of B. garinii from Canada.

Perceptions of the key components of effective, acceptable and accessible services for children and young people experiencing common mental health problems: a qualitative study.

BACKGROUND: Children and young people's (CYP) mental health is a major public health concern internationally and the recent Covid-19 pandemic has amplified these concerns. However, only a minority of CYP receive support from mental health services due to the attitudinal and structural barriers they and their families encounter. For over 20 years, report after report has consistently highlighted the shortcomings of mental health services for CYP in the United Kingdom and attempts to improve services have been largely unsuccessful. The findings reported in this paper are from a multi-stage study that aimed to develop a model of effective, high-quality service design for CYP experiencing common mental health problems. The aim of the stage reported here was to identify CYP's, parents' and service providers' perceptions of the effectiveness, acceptability and accessibility of services. METHODS: Case studies were conducted of nine different services for CYP with common mental health problems in England and Wales. Data were collected using semi-structured interviews with 41 young people, 26 parents and 41 practitioners and were analysed using the Framework approach. Patient and Public Involvement was integrated throughout the study with a group of young co-researchers participating in data collection and analysis. RESULTS: Four key themes defined participants' perceptions of service effectiveness, acceptability and accessibility. Firstly, open access to support with participants highlighting the importance of self-referral, support at the point of need and service availability to CYP/parents. Secondly, the development of therapeutic relationships to promote service engagement which was based on assessment of practitioner's personal qualities, interpersonal skills and mental health expertise and underpinned by relational continuity. Thirdly, personalisation was viewed as promoting service appropriateness and effectiveness by ensuring support was tailored to the individual. Fourthly, the development of self-care skills and mental health literacy helped CYP/parents manage and improve their/their child's mental health problems. CONCLUSIONS: This study contributes to knowledge by identifying four components that are perceived to be central to providing effective, acceptable and accessible mental health services for CYP with common mental health problems irrespective of service model or provider. These components could be used as the foundations for designing and improving services.

Transcriptional dysregulation in developing trigeminal sensory neurons in the LgDel mouse model of DiGeorge 22q11.2 deletion syndrome.

LgDel mice, which model the heterozygous deletion of genes at human chromosome 22q11.2 associated with DiGeorge/22q11.2 deletion syndrome (22q11DS), have cranial nerve and craniofacial dysfunction as well as disrupted suckling, feeding and swallowing, similar to key 22q11DS phenotypes. Divergent trigeminal nerve (CN V) differentiation and altered trigeminal ganglion (CNgV) cellular composition prefigure these disruptions in LgDel embryos. We therefore asked whether a distinct transcriptional state in a specific population of early differentiating LgDel cranial sensory neurons, those in CNgV, a major source of innervation for appropriate oropharyngeal function, underlies this departure from typical development. LgDel versus wild-type (WT) CNgV transcriptomes differ significantly at E10.5 just after the ganglion has coalesced. Some changes parallel altered proportions of cranial placode versus cranial neural crest-derived CNgV cells. Others are consistent with a shift in anterior-posterior patterning associated with divergent LgDel cranial nerve differentiation. The most robust quantitative distinction, however, is statistically verifiable increased variability of expression levels for most of the over 17 000 genes expressed in common in LgDel versus WT CNgV. Thus, quantitative expression changes of functionally relevant genes and increased stochastic variation across the entire CNgV transcriptome at the onset of CN V differentiation prefigure subsequent disruption of cranial nerve differentiation and oropharyngeal function in LgDel mice.

Resolving the deep phylogeny: Implications for early adaptive radiation, cryptic, and present-day ecological diversity of Papuan microhylid frogs.

The microhylid frogs of the New Guinea region are the largest and most ecologically diverse subfamily (Asterophryinae) of one of the largest anuran families in the world and can live in communities of up to 20 species. While there has been recent progress in resolving the phylogenetic relationships of Asterophryinae, significant uncertainties remain, impeding further progress in understanding the evolution of microhabitat use, parental care, and life history variation in this group. In particular, the early divergences at the base of the tree remain unclear; as does the monophyly of some genera; and recent studies have discovered that species with wide geographic distribution are instead cryptic species complexes. In this study, we fortified geographic sampling of the largest previous phylogenetic effort by sequencing an additional 62 taxa and increased data quality and quantity by adding new layers of data vetting and by filling in previously incomplete loci to the five gene dataset (2 mitochondrial, 3 nuclear protein-coding genes) to obtain a dataset that is now 99% complete in over 2400 characters for 233 samples (205 taxa) of Asterophryinae and 3 outgroup taxa, and analyzed microhabitat use data for these taxa from field data and data collected from the literature. Importantly, our sampling includes complete community complements at 19 sites as well as representatives at over 80 sites across New Guinea and its offshore islands. We present a highly resolved molecular phylogeny which, for the first time, has over 95% of nodes supported (84% highly supported) whether using Maximum Likelihood or Bayesian Inference, allowing clarification of all genera (whether monophyletic or clearly not), their sister genera relationships, as well as an age estimate for the Asterophryinae at approximately 20MYA. Early generic diversification occurring between 17 and 12 MYA gave rise to a surprising diversity of about 18 genera as well as the 5 putative microhabitat types. Our tree reveals extensive cryptic diversity calling any widespread taxa into doubt, and clearly demonstrates that complex multispecies communities of Asterophryinae are ecologically diverse, are numerous, and of ancient origin across New Guinea. We discuss the implications of our phylogeny for explaining the explosive diversification of Asterophryinae as the result of adaptive radiation, niche conservatism, and non-adaptive radiation.

Comparative Analysis of Genome of Ehrlichia sp. HF, a Model Bacterium to Study Fatal Human Ehrlichiosis.

BACKGROUND: The genus Ehrlichia consists of tick-borne obligatory intracellular bacteria that can cause deadly diseases of medical and agricultural importance. Ehrlichia sp. HF, isolated from Ixodes ovatus ticks in Japan [also referred to as I. ovatus Ehrlichia (IOE) agent], causes acute fatal infection in laboratory mice that resembles acute fatal human monocytic ehrlichiosis caused by Ehrlichia chaffeensis. As there is no small laboratory animal model to study fatal human ehrlichiosis, Ehrlichia sp. HF provides a needed disease model. However, the inability to culture Ehrlichia sp. HF and the lack of genomic information have been a barrier to advance this animal model. In addition, Ehrlichia sp. HF has several designations in the literature as it lacks a taxonomically recognized name. RESULTS: We stably cultured Ehrlichia sp. HF in canine histiocytic leukemia DH82 cells from the HF strain-infected mice, and determined its complete genome sequence. Ehrlichia sp. HF has a single double-stranded circular chromosome of 1,148,904 bp, which encodes 866 proteins with a similar metabolic potential as E. chaffeensis. Ehrlichia sp. HF encodes homologs of all virulence factors identified in E. chaffeensis, including 23 paralogs of P28/OMP-1 family outer membrane proteins, type IV secretion system apparatus and effector proteins, two-component systems, ankyrin-repeat proteins, and tandem repeat proteins. Ehrlichia sp. HF is a novel species in the genus Ehrlichia, as demonstrated through whole genome comparisons with six representative Ehrlichia species, subspecies, and strains, using average nucleotide identity, digital DNA-DNA hybridization, and core genome alignment sequence identity. CONCLUSIONS: The genome of Ehrlichia sp. HF encodes all known virulence factors found in E. chaffeensis, substantiating it as a model Ehrlichia species to study fatal human ehrlichiosis. Comparisons between Ehrlichia sp. HF and E. chaffeensis will enable identification of in vivo virulence factors that are related to host specificity, disease severity, and host inflammatory responses. We propose to name Ehrlichia sp. HF as Ehrlichia japonica sp. nov. (type strain HF), to denote the geographic region where this bacterium was initially isolated.

Optimal preparation of SARS-CoV-2 viral transport medium for culture.

INTRODUCTION: The sudden arrival of the COVID-19 pandemic placed significant stresses on supply chains including viral transport medium (VTM). The VTM that was urgently required needed to support viral replication, as well as other routine diagnostic approaches. We describe the preparation and validation testing of VTM for rapidly expanding diagnostic testing, where the capacity of the VTM to preserve viral integrity, for culture, isolation and full sequence analysis, was maintained. METHODS: VTM was prepared using different methods of sterilization then 'spiked' with virus. The VTM was investigated using viral culture in Vero cells, and for nucleic acid detection by quantitative PCR. RESULTS: The best results were obtained by filter and autoclave-based sterilization. The VTM proved robust for culture-based analyses provided the inoculated VTM was stored at 4 °C, and tested within 48 h. The filtered VTM also supported PCR-based diagnosis for at least 5 days when the mock inoculated VTM was held at room temperature. DISCUSSION: The manual handling of VTM production, including filling and sterilization, was optimized. SARS-CoV-2 was spiked into VTM to assess different sterilization methods and measure the effects of storage time and temperature upon VTM performance. While most diagnostic protocols will not require replication competent virus, the use of high quality VTM will allow for the next phase of laboratory analysis in the COVID-19 pandemic, including drug and antibody susceptibility analysis of re-isolated SARS-CoV-2, and for the testing of vaccine escape mutants.

Update on maculopathy secondary to pentosan polysulfate toxicity.

PURPOSE OF REVIEW: The aim of the present review is to provide a comprehensive summary of available knowledge regarding toxic maculopathy secondary to pentosan polysulfate sodium (PPS). RECENT FINDINGS: PPS toxicity was described in 2018, and additional studies characterize it as dysfunction of the retinal pigment epithelium centered on the posterior pole, which can progress despite drug cessation. Requisite exposure can be as little as 0.325 kg and 2.25 years but averages closer to 1-2 kg and 10-15 years. Multimodal imaging should include near-infrared reflectance, optical coherence tomography, and fundus autofluorescence. Cross-sectional studies demonstrate evidence correlating cumulative dosing and the likelihood/severity of maculopathy. Early estimates of prevalence range from 12.7 to 41.7% depending on dosing, with overall rates around 20%. SUMMARY: Reasonable evidence associates maculopathy with extended exposure to PPS, with an average reported incidence of around 20% in patients with long-term exposures. Patients with unexplained retinal pigment epithelium changes and difficulty with dark adaptation should be questioned regarding PPS exposure, and patients with known exposure to PPS should be examined. Further research is needed to refine screening protocols. Currently, providers should consider baseline examination and examination at 5 years and/or 500 g of exposure followed by yearly screening.

Changes in the Gut Microbiota Following Bariatric Surgery Are Associated with Increased Alcohol Intake in a Female Rat Model.

AIMS: We aimed to investigate if differences in gut microbiota diversity and composition are associated with post-operative alcohol intake following bariatric surgery in a rat model. METHODS: Twenty-four female rats were randomized to three treatment groups: sham surgery, vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB). Stool was collected pre- and post-operatively and 16S rRNA gene amplification and sequencing was performed. Analysis focused on correlating microbial diversity, type of surgery and alcohol (EtOH) intake. RESULTS: Pre-operative stools samples on regular diet showed similar taxonomic composition and Shannon diversity among the three treatment groups. There was a significant decrease in Shannon diversity and a change in taxonomic composition of the gut microbiota after rats was fed high fat diet. Post-operatively, the RYGB group showed significantly lower taxonomic diversity than the VSG and sham groups, while the VSG and sham groups diversity were not significantly different. Taxonomic composition and function prediction based on PICRUSt analysis showed the RYGB group to be distinct from the VSG and sham groups. Shannon diversity was found to be negatively associated with EtOH intake. CONCLUSIONS: Changes in the taxonomic profile of the gut microbiota following bariatric surgery, particularly RYGB, are associated with increased EtOH intake and may contribute to increased alcohol use disorder risk through the gut-brain-microbiome axis.

What influences practitioners' readiness to deliver psychological interventions by telephone? A qualitative study of behaviour change using the Theoretical Domains Framework.

BACKGROUND: Contemporary health policy is shifting towards remotely delivered care. A growing need to provide effective and accessible services, with maximal population reach has stimulated demand for flexible and efficient service models. The implementation of evidence-based practice has been slow, leaving many services ill equipped to respond to requests for non-face-to-face delivery. To address this translation gap, and provide empirically derived evidence to support large-scale practice change, our study aimed to explore practitioners' perspectives of the factors that enhance the delivery of a NICE-recommended psychological intervention, i.e. guided self-help by telephone (GSH-T), in routine care. We used the Theoretical Domains Framework (TDF) to analyse our data, identify essential behaviour change processes and encourage the successful implementation of remote working in clinical practice. METHOD: Thirty-four psychological wellbeing practitioners (PWPs) from the UK NHS Improving Access to Psychological Therapies (IAPT) services were interviewed. Data were first analysed inductively, with codes cross-matched deductively to the TDF. RESULTS: Analysis identified barriers to the delivery, engagement and implementation of GSH-T, within eight domains from the TDF: (i) Deficits in practitioner knowledge, (ii) Sub-optimal practitioner telephone skills, (iii) Practitioners' lack of beliefs in telephone capabilities and self-confidence, (iv) Practitioners' negative beliefs about consequences, (v) Negative emotions, (vi) Professional role expectations (vii) Negative social influences, and (viii) Challenges in the environmental context and resources. A degree of interdependence was observed between the TDF domains, such that improvements in one domain were often reported to confer secondary advantages in another. CONCLUSIONS: Multiple TDF domains emerge as relevant to improve delivery of GSH-T; and these domains are theoretically and practically interlinked. A multicomponent approach is recommended to facilitate the shift from in-person to telephone-based service delivery models, and prompt behaviour change at practitioner, patient and service levels. At a minimum, the development of practitioners' telephone skills, an increase in clients' awareness of telephone-based treatment, dilution of negative preconceptions about telephone treatment, and robust service level guidance and standards for implementation are required. This is the first study that provides clear direction on how to improve telephone delivery and optimise implementation, aligning with current mental health policy and service improvement.

Correction to: A case of misalignment: the perspectives of local and national decision-makers on the implementation of psychological treatment by telephone in the Improving Access to Psychological Therapies Service.

In the original publication of this article [1], the article title should be revised as blow.

Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions.

On December 17, 2018, the North American branch of the International Life Sciences Institute (ILSI North America) convened a workshop "Can We Begin to Define a Healthy Gut Microbiome Through Quantifiable Characteristics?" with >40 invited academic, government, and industry experts in Washington, DC. The workshop objectives were to 1) develop a collective expert assessment of the state of the evidence on the human gut microbiome and associated human health benefits, 2) see if there was sufficient evidence to establish measurable gut microbiome characteristics that could serve as indicators of "health," 3) identify short- and long-term research needs to fully characterize healthy gut microbiome-host relationships, and 4) publish the findings. Conclusions were as follows: 1) mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; 2) it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease; 3) microbiome communities are highly individualized, show a high degree of interindividual variation to perturbation, and tend to be stable over years; 4) the complexity of microbiome-host interactions requires a comprehensive, multidisciplinary research agenda to elucidate relationships between gut microbiome and host health; 5) biomarkers and/or surrogate indicators of host function and pathogenic processes based on the microbiome need to be determined and validated, along with normal ranges, using approaches similar to those used to establish biomarkers and/or surrogate indicators based on host metabolic phenotypes; 6) future studies measuring responses to an exposure or intervention need to combine validated microbiome-related biomarkers and/or surrogate indicators with multiomics characterization of the microbiome; and 7) because static genetic sampling misses important short- and long-term microbiome-related dynamic changes to host health, future studies must be powered to account for inter- and intraindividual variation and should use repeated measures within individuals.

A Distinct Gut Microbiota Exists Within Crohn's Disease-Related Perianal Fistulae.

BACKGROUND: Gut bacteria are strongly suspected to play a key role in the pathogenesis of Crohn's disease (CD). Studies have demonstrated alterations in the gut microbiota in this patient population. The purpose of this study was to characterize the gut microbiota of fistulizing perianal CD. MATERIALS AND METHODS: Stool and fistula samples were obtained from patients undergoing surgery for CD-related anorectal fistulae. Microbial compositions of matched stool and fistula samples were characterized using 16S rRNA gene profiling. The effect of sample type, patient gender, disease classification (Montreal A/B), disease activity (Harvey Bradshaw Index), antibiotic use, and presence of active proctitis on microbial composition was assessed. RESULTS: Samples were obtained from 18 patients. Bacteroides was the most abundant genera across all samples collected, followed by Streptococcus and Bifidobacterium. Bifidobacterium was present at significantly higher levels in fecal samples than fistula samples, whereas Achromobacter and Corynebacterium were present at significantly higher levels in fistula samples. Antibiotic, but not thiopurine or antitumor necrosis factor medication, exposure affected the gut microbial composition. Patient gender, disease classification, disease activity, and presence of active proctitis did not alter stool or fistula microbiota. CONCLUSIONS: Our data show that the gut microbiota within CD-related anorectal fistulae is distinct from that in stool samples obtained from the same patients. We also observe a dysbiosis in patients treated with antibiotics compared with those not treated with antibiotics.

Effectiveness of the spaced education pedagogy for clinicians' continuing professional development: a systematic review.

CONTEXT: Ensuring clinical practice reflects current evidence is challenging given the rapid proliferation of new knowledge. Changing entrenched clinical behaviours and facilitating the adoption of best practice evidence requires a range of strategies, including affordable, scalable and effective continuing professional development (CPD). Yet, identifying the CPD delivery method most likely to effectively change and improve patient outcomes is difficult given the variability in the evidence for different learning approaches. Although there is moderate level evidence for outreach education, audit and feedback, and face-to-face or online learning, little is known about the capacity of spaced education to change ineffective clinical practice(s). Spaced education harnesses the power of spacing, repetition and testing learning content to increase topic-specific knowledge. Although spaced education is widely used in undergraduate and postgraduate medical programmes, its effectiveness as a CPD delivery method that improves patient outcomes is less certain. AIM: To determine the effectiveness of the spaced education CPD programmes to change targeted clinical knowledge and practice(s) to improve patient outcomes. METHOD: A systematic review, appraising the spaced education CPD evidence generated from searching six specialist medical and psychosocial databases. Studies published in English peer-reviewed journals from 1 January, 2000 to 31 August, 2018 were eligible for inclusion. A modified Kirkpatrick four levels of evaluation framework assisted with appraising the effect of spaced education CPD interventions on clinicians and patients. RESULTS: Of the 2396 studies identified, 17 met the inclusion criteria, involving 2701 practising clinicians from multiple disciplines and specialties. Five randomised controlled trials generated level II evidence, with the remaining 12 studies generating lower levels of evidence. The majority of studies (n = 14) involved the delivery of online spaced education. All studies were evaluated using the modified Kirkpatrick four levels of evaluation framework with: 10 studies demonstrating significant increases in participants' knowledge; seven studies reporting significant changes in clinician behaviour; four studies showing significant increases in clinician confidence; and three studies identifying significant and sustained increases in participants' clinical skills. Only two studies reported positive improvements in patient outcomes. CONCLUSION: Spaced education via an online platform offers a scalable CPD format that can increase clinical knowledge and change practice. However, further adequately powered randomised controlled trials are required to confirm that spaced education CPD can impact positively on patients' reported outcomes.

Implementing an intervention designed to enhance service user involvement in mental health care planning: a qualitative process evaluation.

PURPOSE: Shared decision-making (SDM) and the wider elements of intersecting professional and lay practices are seen as necessary components in the implementation of mental health interventions. A randomised controlled trial of a user- and carer-informed training package in the United Kingdom to enhance SDM in care planning in secondary mental health care settings showed no effect on patient-level outcomes. This paper reports on the parallel process evaluation to establish the influences on implementation at service user, carer, mental health professional and organisational levels. METHODS: A longitudinal, qualitative process evaluation incorporating 134 semi-structured interviews with 54 mental health service users, carers and professionals was conducted. Interviews were undertaken at baseline and repeated at 6 and 12 months post-intervention. Interviews were digitally audio-recorded, transcribed verbatim and analysed thematically. RESULTS: The process evaluation demonstrated that despite buy-in from those delivering care planning in mental health services, there was a failure of training to become embedded and normalised in local provision. This was due to a lack of organisational readiness to accept change combined with an underestimation and lack of investment in the amount and range of relational work required to successfully enact the intervention. CONCLUSIONS: Future aspirations of SDM enactment need to place the circumstances and everyday practices of stakeholders at the centre of implementation. Such studies should consider the historical and current context of health care relationships and include elements which seek to address these directly.

A case of misalignment: the perspectives of local and national decision-makers on the implementation of psychological treatment by telephone in the Improving Access to Psychological Therapies Service.

BACKGROUND: Psychological treatment delivered by telephone is recommended by the National Institute for Health and Care Excellence (NICE) for mild to moderate depression and anxiety, and forms a key part of the Improving Access to Psychological Therapy (IAPT) programme in the UK. Despite evidence of clinical effectiveness, patient engagement is often not maintained and psychological wellbeing practitioners (PWPs) report lacking confidence and training to deliver treatment by telephone. This study aimed to explore the perspectives of professional decision makers (both local and national) on the barriers and facilitators to the implementation of telephone treatment in IAPT. METHODS: Sixteen semi-structured qualitative telephone interviews and one focus group were carried out with decision makers (n = 21) who were involved locally and nationally in policy, practice and research. The interviews and focus group were coded thematically, and then mapped onto the four core constructs of Normalisation Process Theory (NPT). RESULTS: The use of telephone for psychological treatment was universally recognised amongst participants as beneficial for improving patient choice and access to treatment. However, at service level, motives for the implementation of telephone treatments are often misaligned with national objectives. Pressure to meet performance targets has become a key driver for the use of telephone treatment, with promises of increased efficiency and cost savings. These service-focussed objectives challenge the integration of telephone treatments, and PWP acceptance of telephone treatments as non-inferior to face-to-face. Ambivalence among a workforce often lacking the confidence to deliver telephone treatments leads to reluctance among PWPs to 'sell' treatments to a patient population who are not generally expecting treatment in this form. CONCLUSIONS: Perceptions of a need to 'sell' telephone treatment in IAPT persist from top-level decision makers down to frontline practitioners, despite their conflicting motives for the use of telephone. The need for advocacy to highlight the clinical benefit of telephone treatment, along with adequate workforce support and guidance on best practice for implementation is critical to the ongoing success and sustainability of telephone treatment in primary care mental health programmes.

Telephone cognitive behavioural therapy to prevent the development of chronic widespread pain: a qualitative study of patient perspectives and treatment acceptability.

BACKGROUND: Telephone cognitive behavioural therapy (tCBT) is an acceptable and effective treatment for patients with chronic widespread pain (CWP). Preventing the onset of CWP offers considerable benefits to the individual and society and the MAmMOTH study is the first aimed at CWP prevention. The study is a two-arm randomised trial testing a course of tCBT against usual care for prevention of CWP. This nested qualitative study explores patients' treatment experiences, with a view to understanding their potential influences on acceptability of the intervention. METHODS: The MAmMOTH Study recruited 1002 participants, half of whom were randomised to receive tCBT. Participants were eligible for invitation to the trial if they had pain for which they had consulted their GP, or had pain and visited a doctor frequently, and had 2 of 3 risk factors for development of CWP. Participants randomised to tCBT who had completed treatment were eligible for invitation to qualitative interviews for this study. Individual qualitative interviews were conducted with a sub-sample (n = 33) of patients at high risk of developing CWP who had been allocated to the intervention arm. Semi-structured telephone interviews explored treatment experiences and intervention acceptability. Data was analysed using Framework analysis. RESULTS: Participants presented with a range of musculoskeletal and auto-immune conditions and almost half described their pain as 'chronic' on study entry. Many participants perceived the trial intervention to be aimed at treatment of pain rather than prevention of pain. Initial expectations prior to treatment varied, with scepticism more likely for those who had little prior knowledge of CBT approaches. All participants provided positive feedback post intervention particularly in relation to the modality, therapist experience and skills and the intervention. The majority of participants described positive changes in either their subjective level of pain or pain-management post-intervention and some attributed the positive change directly to the intervention as a result of empowerment, increased self-management and cognitive restructuring. CONCLUSIONS: This study extends our understanding of the acceptability and suitability of preventative interventions for chronic widespread pain and provides further evidence for the acceptability of tCBT. TRIAL REGISTRATION: Clinical Trials.gov NCT02668003 (registered 29th January, 2016).

Primordial origin and diversification of plasmids in Lyme disease agent bacteria.

BACKGROUND: With approximately one-third of their genomes consisting of linear and circular plasmids, the Lyme disease agent cluster of species has the most complex genomes among known bacteria. We report here a comparative analysis of plasmids in eleven Borreliella (also known as Borrelia burgdorferi sensu lato) species. RESULTS: We sequenced the complete genomes of two B. afzelii, two B. garinii, and individual B. spielmanii, B. bissettiae, B. valaisiana and B. finlandensis isolates. These individual isolates carry between seven and sixteen plasmids, and together harbor 99 plasmids. We report here a comparative analysis of these plasmids, along with 70 additional Borreliella plasmids available in the public sequence databases. We identify only one new putative plasmid compatibility type (the 30th) among these 169 plasmid sequences, suggesting that all or nearly all such types have now been discovered. We find that the linear plasmids in the non-B. burgdorferi species have undergone the same kinds of apparently random, chaotic rearrangements mediated by non-homologous recombination that we previously discovered in B. burgdorferi. These rearrangements occurred independently in the different species lineages, and they, along with an expanded chromosomal phylogeny reported here, allow the identification of several whole plasmid transfer events among these species. Phylogenetic analyses of the plasmid partition genes show that a majority of the plasmid compatibility types arose early, most likely before separation of the Lyme agent Borreliella and relapsing fever Borrelia clades, and this, with occasional cross species plasmid transfers, has resulted in few if any species-specific or geographic region-specific Borreliella plasmid types. CONCLUSIONS: The primordial origin and persistent maintenance of the Borreliella plasmid types support their functional indispensability as well as evolutionary roles in facilitating genome diversity. The improved resolution of Borreliella plasmid phylogeny based on conserved partition-gene clusters will lead to better determination of gene orthology which is essential for prediction of biological function, and it will provide a basis for inferring detailed evolutionary mechanisms of Borreliella genomic variability including homologous gene and plasmid exchanges as well as non-homologous rearrangements.