Change in incidence rates for psychosis in different ethnic groups in south London: findings from the Clinical Record Interactive Search-First Episode Psychosis (CRIS-FEP) study

Background: A higher incidence of psychotic disorders has been consistently reported among black and other minority ethnic groups, particularly in northern Europe. It is unclear whether these rates have changed over time. Methods: We identified all individuals with a first episode psychosis who presented to adult mental health services between 1 May 2010 and 30 April 2012 and who were resident in London boroughs of Lambeth and Southwark. We estimated age-and-gender standardised incidence rates overall and by ethnic group, then compared our findings to those reported in the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (ÆSOP) study that we carried out in the same catchment area around 10 years earlier. Results: From 9109 clinical records we identified 558 patients with first episode psychosis. Compared with ÆSOP, the overall incidence rates of psychotic disorder in southeast London have increased from 49.4 (95% confidence interval (CI) 43.6–55.3) to 63.1 (95% CI 57.3–69.0) per 100 000 person-years at risk. However, the overall incidence rate ratios (IRR) were reduced in some ethnic groups: for example, IRR (95% CI) for the black Caribbean group reduced from 6.7 (5.4–8.3) to 2.8 (2.1–3.6) and the ‘mixed’ group from 2.7 (1.8–4.2) to 1.4 (0.9–2.1). In the black African group, there was a negligible difference from 4.1 (3.2–5.3) to 3.5 (2.8–4.5). Conclusions: We found that incidence rates of psychosis have increased over time, and the IRR varied by the ethnic group. Future studies are needed to investigate more changes over time and determinants of change

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis

Comparison of TALE designer transcription factors and the CRISPR/dCas9 in regulation of gene expression by targeting enhancers

© The Author(s) 2014. The transcription activator-like effectors (TALEs) and the RNA-guided clustered regularly interspaced short palindromic repeat (CRISPR) associated protein (Cas9) utlil ize distinct molecular mechanisms in targeting site recognition. The two proteins can be modified to carry additional functional domains to regulate expression of genomic loci in mammalian cells. In this study, we have compared the two systems in activation and suppression of the Oct4 and Nanog loci by targeting their enhancers. Although both are able to efficiently activate the luciferase reporters, the CRISPR/dCas9 system is much less potent in activating the endogenous loci and in the application of reprogramming somatic cells to iPS cells. Nevertheless, repression by CRISPR/dCas9 is comparable to or even better than TALE repressors. We demonstrated that dCas9 protein binding results in significant physical interference to binding of native transcription factors at enhancer, less efficient active histone markers induction or recruitment of activating complexes in gene activation. This study thus highlighted the merits and drawbacks of transcription regulation by each system. A combined approach of TALEs and CRISPR/dCas9 should provide an optimized solution to regulate genomic loci and to study genetic elements such as enhancers in biological processes including somatic cell reprogramming and guided differentiation.Link_to_subscribed_fulltex

Reprogramming to pluripotency using designer TALE transcription factors targeting enhancers

The modular DNA recognition code of the transcription-activator-like effectors (TALEs) from plant pathogenic bacterial genus Xanthomonas provides a powerful genetic tool to create designer transcription factors (dTFs) targeting specific DNA sequences for manipulating gene expression. Previous studies have suggested critical roles of enhancers in gene regulation and reprogramming. Here, we report dTF activator targeting the distal enhancer of the Pou5f1 (Oct4) locus induces epigenetic changes, reactivates its expression, and substitutes exogenous OCT4 in reprogramming mouse embryonic fibroblast cells (MEFs) to induced pluripotent stem cells (iPSCs). Similarly, dTF activator targeting a Nanog enhancer activates Nanog expression and reprograms epiblast stem cells (EpiSCs) to iPSCs. Conversely, dTF repressors targeting the same genetic elements inhibit expression of these loci, and effectively block reprogramming. This study indicates that dTFs targeting specific enhancers can be used to study other biological processes such as transdifferentiation or directed differentiation of stem cells. © 2013 The Authors.Link_to_subscribed_fulltex

Assessment of contour variability in target volumes and organs at risk in lung cancer radiotherapy

Aims This study aimed to examine whether any significant differences existed in trial protocol compliance in target volumes (TV) and organs at risk (OARs) contouring amongst clinical oncologists specialised in lung cancer radiotherapy. Materials/methods Two lung radiotherapy trials that require all prospective investigators to submit pre-trial outlining quality assurance (QA) benchmark cases were selected. The contours from the benchmark cases were compared against a set of reference contours which were defined by the trial management group (TMG). In order to quantify the degree of variation in TV and OARs contouring, the matching index (MI), Dice coefficient (DICE), Jaccard index (JI), Van‘t Riet Index and geographical miss index (GMI) were calculated. Results A total of 198 structures contoured by 21 clinicians were collected from the outlining benchmark cases. There were 40 clinical target volumes (CTV), 32 spinal cord, 36 oesophagus, 36 heart and 54 lungs volumes included in the study. Analysis of the pre-trial benchmark cases revealed statistically significant differences (p ≤ 0.05) in trial protocol compliances between clinical oncologists’ target volume and organs at risk contours. Our results demonstrated that the lung contours had the highest level of conformity, followed by heart, CTV, spinal cord and oesophagus respectively. Conclusions This study showed that there was a statistically significant difference in trial protocol compliance for lung clinical oncologists’ TV and OARs contouring within the pre-trial QA benchmark cases. Trial protocol compliances of TV and OARs delineation can be identified through assessing outlining QA benchmark cases

Development and evaluation of a de-identification procedure for a case register sourced from mental health electronic records

Background: Electronic health records (EHRs) provide enormous potential for health research but also present data governance challenges. Ensuring de-identification is a pre-requisite for use of EHR data without prior consent. The South London and Maudsley NHS Trust (SLaM), one of the largest secondary mental healthcare providers in Europe, has developed, from its EHRs, a de-identified psychiatric case register, the Clinical Record Interactive Search (CRIS), for secondary research. Methods: We describe development, implementation and evaluation of a bespoke de-identification algorithm used to create the register. It is designed to create dictionaries using patient identifiers (PIs) entered into dedicated source fields and then identify, match and mask them (with ZZZZZ) when they appear in medical texts. We deemed this approach would be effective, given high coverage of PI in the dedicated fields and the effectiveness of the masking combined with elements of a security model. We conducted two separate performance tests i) to test performance of the algorithm in masking individual true PIs entered in dedicated fields and then found in text (using 500 patient notes) and ii) to compare the performance of the CRIS pattern matching algorithm with a machine learning algorithm, called the MITRE Identification Scrubber Toolkit – MIST (using 70 patient notes – 50 notes to train, 20 notes to test on). We also report any incidences of potential breaches, defined by occurrences of 3 or more true or apparent PIs in the same patient’s notes (and in an additional set of longitudinal notes for 50 patients); and we consider the possibility of inferring information despite de-identification. Results: True PIs were masked with 98.8% precision and 97.6% recall. As anticipated, potential PIs did appear, owing to misspellings entered within the EHRs. We found one potential breach. In a separate performance test, with a different set of notes, CRIS yielded 100% precision and 88.5% recall, while MIST yielded a 95.1% and 78.1%, respectively. We discuss how we overcome the realistic possibility – albeit of low probability – of potential breaches through implementation of the security model. Conclusion: CRIS is a de-identified psychiatric database sourced from EHRs, which protects patient anonymity and maximises data available for research. CRIS demonstrates the advantage of combining an effective de-identification algorithm with a carefully designed security model. The paper advances much needed discussion of EHR de-identification – particularly in relation to criteria to assess de-identification, and considering the contexts of de-identified research databases when assessing the risk of breaches of confidential patient information

A Lethal Sequelae of Spinal Infection Complicating Surgery and Radiotherapy for Head and Neck Cancer

Patients who have undergone neck dissection and radiotherapy are at risk of cervical spine infections. Furthermore, previous radiotherapy and cervical spine infections can lead to fistula formation to the subarachnoid space and intracranial infection. This report discusses the serious consequences of a missed cervical spine infection including cerebrospinal fluid fistula formation and persistent central nervous system infection, and serves as a reminder to clinicians of the possible association between cervical spine infections and prior head and neck surgery and radiotherapy. In all such cases, the posterior pharyngeal wall should be inspected during follow-up. Despite the appearance of an intracranial infection, the cervical spine should be investigated, especially if the response to appropriate antibiotics is suboptimal

Single Cell RNA-Sequencing of Pluripotent States Unlocks Modular Transcriptional Variation

SummaryEmbryonic stem cell (ESC) culture conditions are important for maintaining long-term self-renewal, and they influence cellular pluripotency state. Here, we report single cell RNA-sequencing of mESCs cultured in three different conditions: serum, 2i, and the alternative ground state a2i. We find that the cellular transcriptomes of cells grown in these conditions are distinct, with 2i being the most similar to blastocyst cells and including a subpopulation resembling the two-cell embryo state. Overall levels of intercellular gene expression heterogeneity are comparable across the three conditions. However, this masks variable expression of pluripotency genes in serum cells and homogeneous expression in 2i and a2i cells. Additionally, genes related to the cell cycle are more variably expressed in the 2i and a2i conditions. Mining of our dataset for correlations in gene expression allowed us to identify additional components of the pluripotency network, including Ptma and Zfp640, illustrating its value as a resource for future discovery

Evidence of individual differences in the long-term social, psychological, and cognitive consequences of child maltreatment

Background: The prevalence and consequences of child maltreatment are alarming, but evidence from studies with long follow-up intervals are limited. This study examined the long-term consequences of child maltreatment in relation to age of onset and follow-up interval. / Methods: The exposed group comprised 63 individuals (aged 13–34 years) with a first-time diagnosis of child maltreatment between 2001 and 2010, whereas the unexposed group comprised 63 individuals who were matched upon gender, age of onset, follow-up period, and poverty status at the index hospital admission but had no medical records of maltreatment in Hong Kong. The participants completed a set of questionnaires on executive functions and mental health and provided blood samples for measurement of IL-6 and IL-10 levels during a health assessment session. / Results: Compared with the unexposed group, the exposed group reported poorer maternal care during childhood (β = −4.64, p < 0.001) and had lower family support (β = −2.97, p = 0.010) and higher inflammatory responses (IL-6: β = 0.15, p = 0.001; IL-10: β = 0.11, p = 0.011) at follow-up. Additionally, the associations of childhood maltreatment exposure with family support and maternal care differed by age of onset and the length of time since exposure. / Conclusions: This matched cohort study highlights childhood maltreatment as a risk factor for systemic inflammation and an indicator of suboptimal social environment, both of which could persist over a long period of time