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

Epicutaneous Immunization with Type II Collagen Inhibits both Onset and Progression of Chronic Collagen-Induced Arthritis

Epicutaneous immunization is a potential non-invasive technique for antigen-specific immune-modulation. Topical application of protein antigens to barrier-disrupted skin induces potent antigen-specific immunity with a strong Th2-bias. In this study, we investigate whether the autoimmune inflammatory response of chronic collagen-induced arthritis (CCIA) in DBA/1-TCR-beta Tg mice can be modified by epicutaneous immunization. We show that epicutaneous immunization with type II collagen (CII) inhibited development and progression of CCIA and, importantly, also ameliorated ongoing disease as indicated by clinical scores of disease severity, paw swelling and joints histology. Treated mice show reduced CII-driven T cell proliferation and IFN-gamma production, as well as significantly lower levels of CII-specific IgG2a serum antibodies. In contrast, CII-driven IL-4 production and IgE antibody levels were increased consistent with skewing of the CII response from Th1 to Th2 in treated mice. IL-4 production in treated mice was inversely correlated with disease severity. Moreover, T cells from treated mice inhibited proliferation and IFN-gamma production by T cells from CCIA mice, suggesting induction of regulatory T cells that actively inhibit effector responses in arthritic mice. The levels of CD4(+)CD25(+) T cells were however not increased following epicutaneous CII treatment. Together, these results suggest that epicutaneous immunization may be used as an immune-modulating procedure to actively re-programme pathogenic Th1 responses, and could have potential as a novel specific and simple treatment for chronic autoimmune inflammatory diseases such as rheumatoid arthritis

Ranked prediction of p53 targets using hidden variable dynamic modeling

Full exploitation of microarray data requires hidden information that cannot be extracted using current analysis methodologies. We present a new approach, hidden variable dynamic modeling (HVDM), which derives the hidden profile of a transcription factor from time series microarray data, and generates a ranked list of predicted targets. We applied HVDM to the p53 network, validating predictions experimentally using small interfering RNA. HVDM can be applied in many systems biology contexts to predict regulation of gene activity quantitatively

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

Estranged relations: coercion and care in narratives of supported decision-making in mental healthcare

Supported decision-making has become popular among policymakers and mental health advocates as a means of reducing coercion in mental healthcare. Nevertheless, users of psychiatric services often seem equivocal about the value of supported decision-making initiatives. In this paper we explore why such initiatives might be rejected or ignored by the would-be beneficiaries, and we reflect on broader implications for care and coercion. We take a critical medical humanities approach, particularly through the lens of entanglement. We analyse the narratives of 29 people diagnosed with mental illness, and 29 self-identified carers speaking of their experiences of an Australian mental healthcare system and of their views of supported decision-making. As a scaffolding for our critique we consider two supported decision-making instruments in the 2014 Victorian Mental Health Act: the advance statement and the nominated person. These instruments presuppose that patients and carers endorse a particular set of relationships between the agentic self and illness, as well as between patient, carer and the healthcare system. Our participant narratives instead conveyed ‘entangled’ relations, which we explore in three sections. In the first we show how ideas about fault and illness often coexisted, which corresponded with shifting views on the need for more versus less agency for patients. In the second section, we illustrate how family carers struggled to embody the supported decision-making ideal of the independent yet altruistic nominated person, and in the final section we suggest that both care and coercion were narrated as existing across informal/formal care divisions. We conclude by reflecting on how these dynamic relations complicate supported decision-making projects, and prompt a rethink of how care and coercion unfold in contemporary mental healthcare

Unravelling subjectivity, embodied experience and (taking) psychotropic medication

This paper explores how distinctions between ‘intended’ and ‘side’ effects are troubled in personal narratives of taking psychotropic medications. Grounded in interviews with 29 participants diagnosed with mental illness in Victoria, Australia between February and December 2014, we consider how people interpret pharmaceutical compounds beyond their desired or intended effects, and how such effects shape and transform subjectivity and their relationship with their bodies. This paper contributes to recent discussions of mental illness and medication effects, informed by feminist science studies. It emphasises the co-constitution of social, affective and material relations in the context of ‘taking’ psychotropic medication. This paper discusses three key themes as important to the phenomenology of the nexus of illness and psychotropic medication: movement, ambivalence, and sociality. Our analysis demonstrates how psychotropic drugs are productive of subjectivity through their promises and potential, their unexpected harms and the institutions from which they are inseparable

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

The Case against a Smoker's License

Tobacco continues to kill millions of people around the world each year and its use is increasing in some countries, which makes the need for new, creative, and radical efforts to achieve the tobacco control endgame vitally important. One such effort is discussed in this PLOS Medicine Debate, where Simon Chapman presents his proposal for a "smoker's license" and Jeff Collin argues against. Chapman sets out a case for introducing a smart card license for smokers designed to limit access to tobacco products and encourage cessation. Key elements of the smoker's license include smokers setting daily limits, financial incentives for permanent license surrender, and a test of health risk knowledge for commencing smokers. Collin argues against the proposal, saying that it would shift focus away from the real vector of the epidemic--the tobacco industry--and that by focusing on individuals it would censure victims, increase stigmatization of smokers, and marginalize the poor

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

Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension

Intermittent fasting (IF) can improve function and health during aging in laboratory model organisms, but the mechanisms at work await elucidation. We subjected fruit flies (Drosophila melanogaster) to varying degrees of IF and found that just one month of a 2-day fed:5-day fasted IF regime at the beginning of adulthood was sufficient to extend lifespan. This long-lasting, beneficial effect of early IF was not due to reduced fecundity. Starvation resistance and resistance to oxidative and xenobiotic stress were increased after IF. Early-life IF also led to higher lipid content in 60-day-old flies, a potential explanation for increased longevity. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. Improved gut health was also associated with reduced relative bacterial abundance. Early IF thus induced profound long-term changes. Pharmacological and genetic epistasis analysis showed that IF acted independently of the TOR pathway because rapamycin and IF acted additively to extend lifespan, and global expression of a constitutively active S6K did not attenuate the IF-induced lifespan extension. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health