Predicting CD4 T-cell reconstitution following paediatric haematopoietic stem cell transplantation.

Haematopoietic stem cell transplantation is an increasingly common treatment for children with a range of haematological disorders. Conditioning with cytotoxic chemotherapy and total body irradiation leaves patients severely immunocompromised. T-cell reconstitution can take several years due to delayed restoration of thymic output. Understanding T-cell reconstitution in children is complicated by normal immune system maturation, heterogeneous diagnoses, and sparse uneven sampling due to the long time spans involved. We describe here a mechanistic mathematical model for CD4 T-cell immune reconstitution following pediatric transplantation. Including relevant biology and using mixed-effects modelling allowed the factors affecting reconstitution to be identified. Bayesian predictions for the long-term reconstitution trajectories of individual children were then obtained using early post-transplant data. The model was developed using data from 288 children; its predictive ability validated on data from a further 75 children, with long-term reconstitution predicted accurately in 81% of patients. This article is protected by copyright. All rights reserved

Life expectancy at birth and all-cause mortality among people with personality disorder

Objective: It is well established that serious mental illness is associated with raised mortality, yet few studies have looked at the life expectancy of people with personality disorder (PD). This study aims to examine the life expectancy and relative mortality in people with PD within secondary mental health care. Methods: We set out to examine this using a large psychiatric case register in southeast London, UK. Mortality was obtained through national mortality tracing procedures. In a cohort of patients with a primary diagnosis of PD (n = 1836), standardised mortality ratios (SMRs) and life expectancies at birth were calculated, using general population mortality statistics as the comparator. Results: Life expectancy at birth was 63.3 years for women and 59.1 years for men with PD—18.7 years and 17.7 years shorter than females and males respectively in the general population in England and Wales. The SMR was 4.2 (95% CI: 3.03–5.64) overall; 5.0 (95% CI: 3.15–7.45) for females and 3.5 (95% CI: 2.17–5.47) for males. The highest SMRs were found in the younger age groups for both genders. Conclusion: People with PD using mental health services have a substantially reduced life expectancy, highlighting the significant public health burden of the disorder

Cardiovascular disease treatment among patients with severe mental illness: a data linkage study between primary and secondary care

Background Suboptimal treatment of cardiovascular diseases (CVD) among patients with severe mental illness (SMI) may contribute to physical health disparities. Aim To identify SMI characteristics associated with meeting CVD treatment and prevention guidelines. Design and setting Population-based electronic health record database linkage between primary care and the sole provider of secondary mental health care services in south east London, UK. Method Cardiovascular disease prevalence, risk factor recording, and Quality and Outcomes Framework (QOF) clinical target achievement were compared among 4056 primary care patients with SMI whose records were linked to secondary healthcare records and 270 669 patients without SMI who were not known to secondary care psychiatric services, using multivariate logistic regression modelling. Data available from secondary care records were then used to identify SMI characteristics associated with QOF clinical target achievement. Results Patients with SMI and with coronary heart disease and heart failure experienced reduced prescribing of beta blockers and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB). A diagnosis of schizophrenia, being identified with any indicator of risk or illness severity, and being prescribed with depot injectable antipsychotic medication was associated with the lowest likelihood of prescribing. Conclusion Linking primary and secondary care data allows the identification of patients with SMI most at risk of undertreatment for physical health problems

Naive B cell output in HIV-infected and HIV-uninfected children.

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks-12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks-8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children

Generations of interdisciplinarity in bioinformatics

Bioinformatics, a specialism propelled into relevance by the Human Genome Project and the subsequent -omic turn in the life science, is an interdisciplinary field of research. Qualitative work on the disciplinary identities of bioinformaticians has revealed the tensions involved in work in this “borderland.” As part of our ongoing work on the emergence of bioinformatics, between 2010 and 2011, we conducted a survey of United Kingdom-based academic bioinformaticians. Building on insights drawn from our fieldwork over the past decade, we present results from this survey relevant to a discussion of disciplinary generation and stabilization. Not only is there evidence of an attitudinal divide between the different disciplinary cultures that make up bioinformatics, but there are distinctions between the forerunners, founders and the followers; as inter/disciplines mature, they face challenges that are both inter-disciplinary and inter-generational in nature

Holocene history of the 79° N ice shelf reconstructed from epishelf lake and uplifted glaciomarine sediments

Acknowledgements This work was funded by a NERC standard grant (grant no. NE/N011228/1), and some radiocarbon analysis was funded by NEIF (grant NE/S011587/1; allocation number 2169.1118). We thank the Alfred Wegener Institute, particularly Angelika Humbert and Hicham Rafiq, for significant logistic support through the iGRIFF project. Additional support was provided by Station Nord (Jorgen Skafte), Nordlandair, Air Greenland, and the Joint Arctic Command. Naalakkersuisut (government of Greenland) provided scientific survey (VU-00121) and export (046/2017) licences for this work. Finally, we would like to thank our (Nanu Travel) field ranger Isak (and dog Ooni) for keeping us safe in the field and taking great pleasure in beating James A. Smith at cards. Financial support This research has been supported by the Natural Environment Research Council (grant no. NE/N011228/1).Peer reviewedPublisher PD

Social Science and Neuroscience beyond Interdisciplinarity: Experimental Entanglements

This article is an account of the dynamics of interaction across the social sciences and neurosciences. Against an arid rhetoric of ‘interdisciplinarity’, it calls for a more expansive imaginary of what experiment – as practice and ethos – might offer in this space. Arguing that opportunities for collaboration between social scientists and neuroscientists need to be taken seriously, the article situates itself against existing conceptualizations of these dynamics, grouping them under three rubrics: ‘critique’, ‘ebullience’ and ‘interaction’. Despite their differences, each insists on a distinction between sociocultural and neurobiological knowledge, or does not show how a more entangled field might be realized. The article links this absence to the ‘regime of the inter-’, an ethic of interdisciplinarity that guides interaction between disciplines on the understanding of their pre-existing separateness. The argument of the paper is thus twofold: (1) that, contra the ‘regime of the inter-’, it is no longer practicable to maintain a hygienic separation between sociocultural webs and neurobiological architecture; (2) that the cognitive neuroscientific experiment, as a space of epistemological and ontological excess, offers an opportunity to researchers, from all disciplines, to explore and register this realization

Evolutionary origins of the estrogen signaling system : insights from amphioxus

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Steroid Biochemistry and Molecular Biology 127 (2011): 176–188, doi:10.1016/j.jsbmb.2011.03.022.Classically, the estrogen signaling system has two core components: cytochrome P450 aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in estrogen biosynthesis; and estrogen receptors (ERs), ligand activated transcription factors that interact with the regulatory region of target genes to mediate the biological effects of estrogen. While the importance of estrogens for regulation of reproduction, development and physiology has been well-documented in gnathostome vertebrates, the evolutionary origins of estrogen as a hormone are still unclear. As invertebrates within the phylum Chordata, cephalochordates (e.g. the amphioxus of the genus Branchiostoma) are among the closest invertebrate relatives of the vertebrates and can provide critical insight into the evolution of vertebrate-specific molecules and pathways. To address this question, this paper briefly reviews relevant earlier studies that help to illuminate the history of the aromatase and ER genes, with a particular emphasis on insights from amphioxus and other invertebrates. We then present new analyses of amphioxus aromatase and ER sequence and function, including an in silico model of the amphioxus aromatase protein, and CYP19 gene analysis. CYP19 shares a conserved gene structure with vertebrates (9 coding exons) and moderate sequence conservation (40% amino acid identity with human CYP19). Modeling of the amphioxus aromatase substrate binding site and simulated docking of androstenedione in comparison to the human aromatase shows that the substrate binding site is conserved and predicts that androstenedione could be a substrate for amphioxus CYP19. The amphioxus ER is structurally similar to vertebrate ERs, but differs in sequence and key residues of the ligand binding domain. Consistent with results from other laboratories, amphioxus ER did not bind radiolabeled estradiol, nor did it modulate gene expression on an estrogen-responsive element (ERE) in the presence 59 of estradiol, 4-hydroxytamoxifen, diethylstilbestrol, bisphenol A or genistein. Interestingly, it has been shown that a related gene, the amphioxus “steroid receptor” (SR), can be activated by estrogens and that amphioxus ER can repress this activation. CYP19, ER and SR are all primarily expressed in gonadal tissue, suggesting an ancient paracrine/autocrinesignaling role, but it is not yet known how their expression is regulated and, if estrogen is actually synthesized in amphioxus, whether it has a role in mediating any biological effects . Functional studies are clearly needed to link emerging bioinformatics and in vitro molecular biology results with organismal physiology to develop an understanding of the evolution of estrogen signaling.Supported by grants from the NIEHS P42 ES07381 (GVC, SV) and EPA (STAR-RD831301) (GVC), a Ruth L Kirschstein National Research Service Award (AT, F32 ES013092-01), an NIH traineeship (SS, SG), a NATO Fellowship (AN) and the Boston University Undergraduate Research Program (LC)

Researching Memory in Early Modern Studies

This essay pursues the study of early modern memory across a chronologically, conceptually and thematically broad canvas in order to address key questions about the historicity of memory and the methodologies of memory studies. First, what is the value for our understanding of early modern memory practices of transporting the methodologies of contemporary memory studies backwards, using them to study the memorial culture of a time before living memory? Second, what happens to the cross-disciplinary project of memory studies when it is taken to a distant period, one that had its own highly self-conscious and much debated cultures of remembering? Drawing on evidence and debates from a range of disciplinary locations, but primarily focusing on literary and historical studies, the essay interrogates crucial differences and commonalities between memory studies and early modern studies