Gene therapy for articular cartilage repair

Articular cartilage serves as the gliding surface of joints. It is susceptible to damage from trauma and from degenerative diseases. Restoration of damaged articular cartilage may be achievable through the use of cell-regulatory molecules that augment the reparative activities of the cells, inhibit the cells\u27; degradative activities, or both. A variety of such molecules have been identified. These include insulin-like growth factor I, fibroblast growth factor 2, bone morphogenetic proteins 2, 4, and 7, and interleukin-1 receptor antagonist. It is now possible to transfer the genes encoding such molecules into articular cartilage and synovial lining cells. Although preliminary, data from in-vitro and in-vivo studies suggest that gene therapy can deliver such potentially therapeutic agents to protect existing cartilage and to build new cartilage. Keywords: gene therapy, vectors, articular cartilage, arthritis, animal model

Crisis resolution and home treatment in the UK: A survey of model fidelity using a novel review methodology

Crisis resolution teams (CRTs) provide treatment at home to people experiencing mental health crises, as an alternative to hospital admission. Previous UK research, based on self‐report surveys, suggests that a loosely specified model has resulted in wide variations in CRTs’ service delivery, organization and outcomes. A fidelity scale (developed through evidence review and stakeholder consensus) provided a means of objectively measuring adherence to a model of good practice for CRTs, via one‐day fidelity reviews of UK crisis teams. Reviews included interviews with service users, carers, staff and managers, and examination of data, policies, protocols and anonymized case notes. Of the 75 teams reviewed, 49 (65%) were assessed as being moderate fidelity and the rest as low fidelity, with no team achieving high fidelity. The median score was 122 (range: 73–151; inter‐quartile range: 111–132). Teams achieved higher scores on items about structure and organization, for example ease of referral, medication and safety systems, but scored poorly on items about the content of care and interventions. Despite a national mandate to implement the CRT model, there are wide variations in implementation in the UK and no teams in our sample achieved overall high fidelity. This suggests that a mandatory national policy is not in itself sufficient to achieve good quality implementation of a service model. The CRT Fidelity Scale provides a feasible and acceptable means to objectively assess model fidelity in CRTs. There is a need for development and testing of interventions to enhance model fidelity and facilitate improvements to these services

Ethnic inequalities and pathways to care in psychosis in England: a systematic review and meta-analysis

© The Author(s). 2018Background: As part of a national programme to tackle ethnic inequalities, we conducted a systematic review and meta-analysis of research on ethnic inequalities in pathways to care for adults with psychosis living in England and/or Wales. Methods: Nine databases were searched from inception to 03.07.17 for previous systematic reviews, including forward and backward citation tracking and a PROSPERO search to identify ongoing reviews. We then carried forward relevant primary studies from included reviews (with the latest meta-analyses reporting on research up to 2012), supplemented by a search on 18.10.17 in MEDLINE, Embase, PsycINFO and CINAHL for primary studies between 2012 and 2017 that had not been covered by previous meta-analyses. Results: Forty studies, all conducted in England, were included for our updated meta-analyses on pathways to care. Relative to the White reference group, elevated rates of civil detentions were found for Black Caribbean (OR = 3.43, 95% CI = 2.68 to 4.40, n = 18), Black African (OR = 3.11, 95% CI = 2.40 to 4.02, n = 6), and South Asian patients (OR = 1.50, 95% CI 1.07 to 2.12, n = 10). Analyses of each Mental Health Act section revealed significantly higher rates for Black people under (civil) Section 2 (OR = 1.53, 95% CI = 1.11 to 2.11, n = 3). Rates in repeat admissions were significantly higher than in first admission for South Asian patients (between-group difference p < 0.01). Some ethnic groups had more police contact (Black African OR = 3.60, 95% CI = 2.15 to 6.05, n = 2; Black Caribbean OR = 2.64, 95% CI = 1.88 to 3.72, n = 8) and criminal justice system involvement (Black Caribbean OR = 2.76, 95% CI = 2.02 to 3.78, n = 5; Black African OR = 1.92, 95% CI = 1.32 to 2.78, n = 3). The White Other patients also showed greater police and criminal justice system involvement than White British patients (OR = 1.49, 95% CI = 1.03 to 2.15, n = 4). General practitioner involvement was less likely for Black than the White reference group. No significant variations over time were found across all the main outcomes. Conclusions: Our updated meta-analyses reveal persisting but not significantly worsening patterns of ethnic inequalities in pathways to psychiatric care, particularly affecting Black groups. This provides a comprehensive evidence base from which to inform policy and practice amidst a prospective Mental Health Act reform. Trial registration: CRD42017071663Peer reviewedFinal Published versio

Crisis resolution teams for people experiencing mental health crises: the CORE mixed-methods research programme including two RCTs

Background Crisis resolution teams (CRTs) seek to avert hospital admissions by providing intensive home treatment for people experiencing a mental health crisis. The CRT model has not been highly specified. CRT care is often experienced as ending abruptly and relapse rates following CRT discharge are high. Aims The aims of CORE (Crisis resolution team Optimisation and RElapse prevention) workstream 1 were to specify a model of best practice for CRTs, develop a measure to assess adherence to this model and evaluate service improvement resources to help CRTs implement the model with high fidelity. The aim of CORE workstream 2 was to evaluate a peer-provided self-management programme aimed at reducing relapse following CRT support. Methods Workstream 1 was based on a systematic review, national CRT manager survey and stakeholder qualitative interviews to develop a CRT fidelity scale through a concept mapping process with stakeholders (n = 68). This was piloted in CRTs nationwide (n = 75). A CRT service improvement programme (SIP) was then developed and evaluated in a cluster randomised trial: 15 CRTs received the SIP over 1 year; 10 teams acted as controls. The primary outcome was service user satisfaction. Secondary outcomes included CRT model fidelity, catchment area inpatient admission rates and staff well-being. Workstream 2 was a peer-provided self-management programme that was developed through an iterative process of systematic literature reviewing, stakeholder consultation and preliminary testing. This intervention was evaluated in a randomised controlled trial: 221 participants recruited from CRTs received the intervention and 220 did not. The primary outcome was re-admission to acute care at 1 year of follow-up. Secondary outcomes included time to re-admission and number of days in acute care over 1 year of follow-up and symptoms and personal recovery measured at 4 and 18 months’ follow-up. Results Workstream 1 – a 39-item CRT fidelity scale demonstrated acceptability, face validity and promising inter-rater reliability. CRT implementation in England was highly variable. The SIP trial did not produce a positive result for patient satisfaction [median Client Satisfaction Questionnaire score of 28 in both groups at follow-up; coefficient 0.97, 95% confidence interval (CI) –1.02 to 2.97]. The programme achieved modest increases in model fidelity. Intervention teams achieved lower inpatient admission rates and less inpatient bed use. Qualitative evaluation suggested that the programme was generally well received. Workstream 2 – the trial yielded a statistically significant result for the primary outcome, in which rates of re-admission to acute care over 1 year of follow-up were lower in the intervention group than in the control group (odds ratio 0.66, 95% CI 0.43 to 0.99; p = 0.044). Time to re-admission was lower and satisfaction with care was greater in the intervention group at 4 months’ follow-up. There were no other significant differences between groups in the secondary outcomes. Limitations Limitations in workstream 1 included uncertainty regarding the representativeness of the sample for the primary outcome and lack of blinding for assessment. In workstream 2, the limitations included the complexity of the intervention, preventing clarity about which were effective elements. Conclusions The CRT SIP did not achieve all its aims but showed potential promise as a means to increase CRT model fidelity and reduce inpatient service use. The peer-provided self-management intervention is an effective means to reduce relapse rates for people leaving CRT care. Study registration The randomised controlled trials were registered as Current Controlled Trials ISRCTN47185233 and ISRCTN01027104. The systematic reviews were registered as PROSPERO CRD42013006415 and CRD42017043048. Funding The National Institute for Health Research Programme Grants for Applied Research programme

Visualizing variation within Global Pneumococcal Sequence Clusters (GPSCs) and country population snapshots to contextualize pneumococcal isolates

Knowledge of pneumococcal lineages, their geographic distribution and antibiotic resistance patterns, can give insights into global pneumococcal disease. We provide interactive bioinformatic outputs to explore such topics, aiming to increase dissemination of genomic insights to the wider community, without the need for specialist training. We prepared 12 country-specific phylogenetic snapshots, and international phylogenetic snapshots of 73 common Global Pneumococcal Sequence Clusters (GPSCs) previously defined using PopPUNK, and present them in Microreact. Gene presence and absence defined using Roary, and recombination profiles derived from Gubbins are presented in Phandango for each GPSC. Temporal phylogenetic signal was assessed for each GPSC using BactDating. We provide examples of how such resources can be used. In our example use of a country-specific phylogenetic snapshot we determined that serotype 14 was observed in nine unrelated genetic backgrounds in South Africa. The international phylogenetic snapshot of GPSC9, in which most serotype 14 isolates from South Africa were observed, highlights that there were three independent sub-clusters represented by South African serotype 14 isolates. We estimated from the GPSC9-dated tree that the sub-clusters were each established in South Africa during the 1980s. We show how recombination plots allowed the identification of a 20kb recombination spanning the capsular polysaccharide locus within GPSC97. This was consistent with a switch from serotype 6A to 19A estimated to have occured in the 1990s from the GPSC97-dated tree. Plots of gene presence/absence of resistance genes (tet, erm, cat) across the GPSC23 phylogeny were consistent with acquisition of a composite transposon. We estimated from the GPSC23-dated tree that the acquisition occurred between 1953 and 1975. Finally, we demonstrate the assignment of GPSC31 to 17 externally generated pneumococcal serotype 1 assemblies from Utah via Pathogenwatch. Most of the Utah isolates clustered within GPSC31 in a USA-specific clade with the most recent common ancestor estimated between 1958 and 1981. The resources we have provided can be used to explore to data, test hypothesis and generate new hypotheses. The accessible assignment of GPSCs allows others to contextualize their own collections beyond the data presented here

Bats, Bat Flies, and Fungi: Exploring Uncharted Waters

Bats serve as hosts to many lineages of arthropods, of which the blood-sucking bat flies (Nycteribiidae and Streblidae) are the most conspicuous. Bat flies can in turn be parasitized by Laboulbeniales fungi, which are biotrophs of arthropods. This is a second level of parasitism, hyperparasitism, a severely understudied phenomenon. Four genera of Laboulbeniales are known to occur on bat flies, Arthrorhynchus on Nycteribiidae in the Eastern Hemisphere, Dimeromyces on Old World Streblidae, Gloeandromyces on New World Streblidae, and Nycteromyces on Streblidae in both hemispheres. In this chapter, we introduce the different partners of the tripartite interaction and discuss their species diversity, ecology, and patterns of specificity. We cover parasite prevalence of Laboulbeniales fungi on bat flies, climatic effects on parasitism of bat flies, and coevolutionary patterns. One of the most important questions in this tripartite system is whether habitat has an influence on parasitism of bat flies by Laboulbeniales fungi. We hypothesize that habitat disturbance causes parasite prevalence to increase, in line with the “dilution effect.” This can only be resolved based on large, non-biased datasets. To obtain these, we stress the importance of multitrophic field expeditions and international collaborations

Analyzing the Impacts of Dams on Riparian Ecosystems: A Review of Research Strategies and Their Relevance to the Snake River Through Hells Canyon

River damming provides a dominant human impact on river environments worldwide, and while local impacts of reservoir flooding are immediate, subsequent ecological impacts downstream can be extensive. In this article, we assess seven research strategies for analyzing the impacts of dams and river flow regulation on riparian ecosystems. These include spatial comparisons of (1) upstream versus downstream reaches, (2) progressive downstream patterns, or (3) the dammed river versus an adjacent free-flowing or differently regulated river(s). Temporal comparisons consider (4) pre- versus post-dam, or (5) sequential post-dam conditions. However, spatial comparisons are complicated by the fact that dams are not randomly located, and temporal comparisons are commonly limited by sparse historic information. As a result, comparative approaches are often correlative and vulnerable to confounding factors. To complement these analyses, (6) flow or sediment modifications can be implemented to test causal associations. Finally, (7) process-based modeling represents a predictive approach incorporating hydrogeomorphic processes and their biological consequences. In a case study of Hells Canyon, the upstream versus downstream comparison is confounded by a dramatic geomorphic transition. Comparison of the multiple reaches below the dams should be useful, and the comparison of Snake River with the adjacent free-flowing Salmon River may provide the strongest spatial comparison. A pre- versus post-dam comparison would provide the most direct study approach, but pre-dam information is limited to historic reports and archival photographs. We conclude that multiple study approaches are essential to provide confident interpretations of ecological impacts downstream from dams, and propose a comprehensive study for Hells Canyon that integrates multiple research strategies

Local Abundance Patterns of Noctuid Moths in Olive Orchards: Life-History Traits, Distribution Type and Habitat Interactions

Local species abundance is related to range size, habitat characteristics, distribution type, body size, and life-history variables. In general, habitat generalists and polyphagous species are more abundant in broad geographical areas. Underlying this, local abundance may be explained from the interactions between life-history traits, chorological pattern, and the local habitat characteristics. The relationship within taxa between life-history traits, distribution area, habitat characteristics, and local abundance of the noctuid moth (Lepidoptera: Noctuidae) assemblage in an olive orchard, one of the most important agro-ecosystems in the Mediterranean basin, was analyzed. A total of 66 species were detected over three years of year-round weekly samplings using the light-trap method. The life-history traits examined and the distribution type were found to be related to the habitat-species association, but none of the biological strategies defined from the association to the different habitats were linked with abundance. In contrast to general patterns, dispersal ability and number of generations per year explained differences in abundance. The relationships were positive, with opportunistic taxa that have high mobility and several generations being locally more abundant. In addition, when the effect of migrant species was removed, the distribution type explained abundance differences, with Mediterranean taxa (whose baricenter is closer to the studied area) being more abundant