Preprotachykinin A (PPTA) is expressed by a distinct population of excitatory neurons in the mouse superficial spinal dorsal horn including cells that respond to noxious and pruritic stimuli

The superficial dorsal horn, which is the main target for nociceptive and pruritoceptive primary afferents, contains a high density of excitatory interneurons. Our understanding of their roles in somatosensory processing has been restricted by the difficulty of distinguishing functional populations among these cells. We recently defined three non-overlapping populations among the excitatory neurons, based on the expression of neurotensin, neurokinin B (NKB) and gastrin-releasing peptide (GRP). Here we identify and characterise another population: neurons that express the tachykinin peptide substance P. We show with immunocytochemistry that its precursor protein (preprotachykinin A, PPTA) can be detected in ~14% of lamina I-II neurons, and these are concentrated in the outer part of lamina II. Over 80% of the PPTA-positive cells lack the transcription factor Pax2 (which determines an inhibitory phenotype), and these account for ~15% of the excitatory neurons in this region. They are different from the neurotensin, NKB or GRP neurons, although many of them contain somatostatin, which is widely expressed among superficial dorsal horn excitatory interneurons. We show that many of these cells respond to noxious thermal and mechanical stimuli, and to intradermal injection of pruritogens. Finally, we demonstrate that these cells can also be identified in a knock-in Cre mouse line (Tac1Cre), although our findings suggest that there is an additional population of neurons that transiently express PPTA. This population of substance P-expressing excitatory neurons is likely to play an important role in transmission of signals that are perceived as pain and itch

Introducing and integrating perinatal mental health screening:Development of an equity-informed evidence-based approach

Background: Pregnancy is a time of increased risk for developing or re-experiencing mental illness. Perinatal mental health screening for all women is recommended in many national guidelines, but a number of systems-level and individual barriers often hinder policy implementation. These barriers result in missed opportunities for detection and early intervention and are likely to be experienced disproportionately by women from culturally and linguistically diverse backgrounds, including women of refugee backgrounds. The objectives of this study were to develop a theory-informed, evidence-based guide for introducing and integrating perinatal mental health screening across health settings and to synthesize the learnings from an implementation initiative and multisectoral partnership between the Centre of Perinatal Excellence (COPE), and a university-based research centre. COPE is a nongovernmental organization (NGO) commissioned to update the Australian perinatal mental health guidelines, train health professionals and implement digital screening. Methods: In this case study, barriers to implementation were prospectively identified and strategies to overcome them were developed. A pilot perinatal screening programme for depression and anxiety with a strong health equity focus was implemented and evaluated at a large public maternity service delivering care to a culturally diverse population of women in metropolitan Melbourne, Australia, including women of refugee background. Strategies that were identified preimplementation and postevaluation were mapped to theoretical frameworks. An implementation guide was developed to support future policy, planning and decision-making by healthcare organizations. Results: Using a behavioural change framework (Capability, Opportunity, Motivation–Behaviour Model), the key barriers, processes and outcomes are described for a real-world example designed to maximize accessibility, feasibility and acceptability. A Programme Logic Model was developed to demonstrate the relationships of the inputs, which included stakeholder consultation, resource development and a digital screening platform, with the outcomes of the programme. A seven-stage implementation guide is presented for use in a range of healthcare settings. Conclusions: These findings describe an equity-informed, evidence-based approach that can be used by healthcare organizations to address common systems and individual-level barriers to implement perinatal depression and anxiety screening guidelines. Patient or Public Contribution: These results present strategies that were informed by prior research involving patients and staff from a large public antenatal clinic in Melbourne, Australia. This involved interviews with health professionals from the clinic such as midwives, obstetricians, perinatal mental health and refugee health experts and interpreters. Interviews were also conducted with women of refugee background who were attending the clinic for antenatal care. A steering committee was formed to facilitate the implementation of the perinatal mental health screening programme comprising staff from key hospital departments, GP liaison, refugee health and well-being, the NGO COPE and academic experts in psychology, midwifery, obstetrics and public health. This committee met fortnightly for 2 years to devise strategies to address the barriers, implement and evaluate the programme. A community advisory group was also formed that involved women from eight different countries, some of refugee background, who had recently given birth at the health service. This committee met bimonthly and was instrumental in planning the implementation and evaluation such as recruitment strategies, resources and facilitating an understanding of the cultural complexity of the women participating in the study.</p

Introducing and integrating perinatal mental health screening:Development of an equity-informed evidence-based approach

Background: Pregnancy is a time of increased risk for developing or re-experiencing mental illness. Perinatal mental health screening for all women is recommended in many national guidelines, but a number of systems-level and individual barriers often hinder policy implementation. These barriers result in missed opportunities for detection and early intervention and are likely to be experienced disproportionately by women from culturally and linguistically diverse backgrounds, including women of refugee backgrounds. The objectives of this study were to develop a theory-informed, evidence-based guide for introducing and integrating perinatal mental health screening across health settings and to synthesize the learnings from an implementation initiative and multisectoral partnership between the Centre of Perinatal Excellence (COPE), and a university-based research centre. COPE is a nongovernmental organization (NGO) commissioned to update the Australian perinatal mental health guidelines, train health professionals and implement digital screening. Methods: In this case study, barriers to implementation were prospectively identified and strategies to overcome them were developed. A pilot perinatal screening programme for depression and anxiety with a strong health equity focus was implemented and evaluated at a large public maternity service delivering care to a culturally diverse population of women in metropolitan Melbourne, Australia, including women of refugee background. Strategies that were identified preimplementation and postevaluation were mapped to theoretical frameworks. An implementation guide was developed to support future policy, planning and decision-making by healthcare organizations. Results: Using a behavioural change framework (Capability, Opportunity, Motivation–Behaviour Model), the key barriers, processes and outcomes are described for a real-world example designed to maximize accessibility, feasibility and acceptability. A Programme Logic Model was developed to demonstrate the relationships of the inputs, which included stakeholder consultation, resource development and a digital screening platform, with the outcomes of the programme. A seven-stage implementation guide is presented for use in a range of healthcare settings. Conclusions: These findings describe an equity-informed, evidence-based approach that can be used by healthcare organizations to address common systems and individual-level barriers to implement perinatal depression and anxiety screening guidelines. Patient or Public Contribution: These results present strategies that were informed by prior research involving patients and staff from a large public antenatal clinic in Melbourne, Australia. This involved interviews with health professionals from the clinic such as midwives, obstetricians, perinatal mental health and refugee health experts and interpreters. Interviews were also conducted with women of refugee background who were attending the clinic for antenatal care. A steering committee was formed to facilitate the implementation of the perinatal mental health screening programme comprising staff from key hospital departments, GP liaison, refugee health and well-being, the NGO COPE and academic experts in psychology, midwifery, obstetrics and public health. This committee met fortnightly for 2 years to devise strategies to address the barriers, implement and evaluate the programme. A community advisory group was also formed that involved women from eight different countries, some of refugee background, who had recently given birth at the health service. This committee met bimonthly and was instrumental in planning the implementation and evaluation such as recruitment strategies, resources and facilitating an understanding of the cultural complexity of the women participating in the study.</p

Discovery of a luminous white dwarf in a young star cluster in the Large Magellanic Cloud

We have identified a candidate 1-2 x 10^5 year old luminous white dwarf in NGC 1818, a young star cluster in the Large Magellanic Cloud. This discovery strongly constrains the boundary mass M_c at which stars stop forming neutron stars and start forming white dwarfs, to M_c > 7.6 Msun.Comment: 4 pages, 2 figures, greyscale image available by ftp from [email protected]. ApJLetters, accepted 17 March 199

Perinatal mental health screening for women of refugee background:Addressing a major gap in pregnancy care

Background: Perinatal mental health disorders affect up to 20% of all women. Women of refugee background are likely to be at increased risk, yet little research has explored this. This study aimed to assess if women of refugee background are more likely to screen risk positive for depression and anxiety than non-refugee women, using the Edinburgh Postnatal Depression Scale (EPDS); and if screening in pregnancy using the EPDS enables better detection of depression and anxiety symptoms in women of refugee background than routine care. Methods: This implementation study was conducted at an antenatal clinic in Melbourne, Australia. Women of refugee and non-refugee backgrounds were screened for depression using English or translated versions of the EPDS and a psychosocial assessment on a digital platform. The psychosocial assessment records of 34 women of refugee background receiving routine care (no screening) were audited. Results: Overall, 274 women completed the EPDS; 43% of refugee background. A similar proportion of women of refugee and non-refugee backgrounds had EPDS scores of ≥9 (39% vs. 40% p = 0.93). Women receiving the combined EPDS and psychosocial screening were more likely to receive a referral for further support than women receiving routine care (41% vs. 18%, p = 0.012). Conclusion: Similarly, high proportions of women of refugee and non-refugee backgrounds were at increased risk of experiencing a current depressive disorder in early pregnancy, suggesting pregnancy care systems should acknowledge and respond to the mental health needs of these women. Screening appeared to facilitate the identification and referral of women compared to routine care.</p

Systematic review and meta-analysis : the prevalence of mental illness in child and adolescent refugees and asylum seekers

Objective Over half of the world’s refugee population are under the age of 18 years. This systematic review aims to summarise the current body of evidence for the prevalence of mental illness in child and adolescent refugee populations. Method Eight electronic databases, grey literature, and Google Scholar were searched for articles from 1 January 2003 to 5 February 2018. Strict inclusion criteria regarding the diagnosis of mental illness were imposed. Study quality was assessed using a template according to study design, and study heterogeneity using I2 statistic. Random effects meta-analyses results were presented given heterogeneity among studies. The protocol for this systematic review was registered with PROSPERO (CRD42016046349). Results Eight studies were eligible, involving 779 child and adolescent refugees and asylum seekers, with studies conducted in five countries. The overall prevalence of post-traumatic stress disorder (PTSD) was 22.71% (95% CI 12.79-32.64), depression 13.81% (95% CI 5.96-21.67), and anxiety disorders 15.77% (95% CI 8.04-23.50). Attention-deficit/hyperactivity disorder (ADHD) was 8.6% (1.08-16.12) and oppositional defiant disorder (ODD) was 1.69% (95% CI -0.78 – 4.16). Due to high heterogeneity, further subgroup analyses were conducted. Conclusion Refugee and asylum seeker children have high rates of PTSD, depression, and anxiety. Without the serious commitment by health and resettlement services to provide early support to promote mental health, these findings suggest a high proportion of refugee children are at risk of educational disadvantage and poor social integration in host communities, potentially affecting their life course

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS)

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.Peer Reviewed"Article signat per 22 autors/es: Martin A. M. Reijns, David A. Parry, Thomas C. Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Hang Xiang, Kate Ridout, The Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project, Anna Schuh, Konrad Aden, Claire Palles, Elias Campo, Tatjana Stankovic, Martin S. Taylor & Andrew P. Jackson "Postprint (published version