Lifetime affective symptoms and mortality in the MRC National Survey of Health and Development

This thesis investigated associations between lifetime affective symptoms and mortality in the MRC National Survey of Health and Development (NSHD; the British 1946 birth cohort). Affective symptoms were initially rated by teachers when study members were aged 13 and 15; then by semi-structured clinical interview at age 36 using the Present State Examination (PSE); the interview-based Psychiatric Frequency Questionnaire at age 43; and the self-report 28-item General Health Questionnaire at age 53. Mortality data including cause of death was obtained from the NHS Central Register. Follow-up time was from ages of exposure to end of October 2014 (age 68). A wide range of covariates were tested, including sex; early life factors; adult health indicators and health behaviours; psychotropic medication; stressful life events, and social factors. Cox regression showed that after adjustment for sex, severe affective symptoms were associated with an increased risk of mortality compared to those with no or mild symptoms across most ages. There was evidence of an accumulation effect where the risk of mortality increased as affective caseness increased. Adolescent-only, intermittent and chronic caseness were associated with increased risk of mortality compared to those who were never a case. There was a slightly stronger association between affective caseness and cardiovascular mortality compared to cancer mortality; however the strongest associations appeared to be with respect to deaths from ‘other’ causes. After full adjustment, those who were a case at a single point in time and those with adolescent-only caseness had a 46% and 73% increased risk of mortality respectively, compared to those who were never a case. All other associations were largely explained by the covariates, with most relationships attenuated predominantly by self-reported health conditions, physical activity, lung function, smoking, and psychotropic medication use. These results demonstrate the inherent interplay between affective symptoms and physical health, and highlight the importance of early intervention in order to reduce health inequalities

Pronunciation models in regional environments: a comparison and assessment of RP and SSE

For many years, the native speaker of English has been exclusively seen as the ‘standard’ or preferred pronunciation model of choice for L2 users of English, and the accent known as Standard British English, also called Received Pronunciation (RP), was seen as the normative. However, in environments where the aforementioned model has ‘a negligible number of speakers’ (Brown, 1991) and could even be described as ‘phantom’ (Daniels, 1995), the question of whether RP supports student perception and production better than a local standard model is particularly relevant. Scotland, with its range of academic institutions and growing number of international students could be considered such an environment. In order to establish the most appropriate model for L2 students studying in Scotland, a 5-week explicit pronunciation study was conducted, with international students being exposed to 10 hours of pre-recorded pronunciation instruction with either an RP or a Scottish Standard English (SSE) model. Prior to beginning, and upon culmination of the course, students undertook diagnostic and summative testing in which perception and production of a range of pre-selected segmental and suprasegmental features was assessed. A control group was also assessed in order to establish whether any improvements in scores that occurred were due to the explicit pronunciation tuition, or were simply instances of implicit learning which developed upon exposure to the 21 hours of weekly English tuition all participants were receiving on their pre-sessional course. Having been quantitatively analysed, test results show that after 5 weeks all groups, including the controls, made significant increases in their perception of Nuclear stress. There were also surprising significant increases in the perception of the tested, but not taught, segmental ɔ/O in the SSE and control group suggesting the occurrence of implicit learning. However, in terms of production, while results hint at a positive trend among SSE students, the RP group made the most significant increase in score after 5 weeks. This contrasts with the Control group’s results which decreased over the same time period

Increased risk of depression in non-depressed HIV infected men with sleep disturbance: Prospective findings from the Multicenter AIDS Cohort Study.

ObjectiveSleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-).MethodsUsing data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared.ResultsIn the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P < .05) than in HIV- MSM (OR = 1.16; 95% CI, 0.94, 1.44). HIV status and sleep disturbance interacted (P < .001), such that incidence of depression and normalized cumulative rate of depression were greater in HIV+ with sleep disturbance than in HIV+ without sleep disturbance and HIV- groups (all P's < 0.001).ConclusionsHIV+ persons who report sleep disturbance represent a high risk group to be monitored for depression, and possibly targeted for insomnia treatment to prevent depression. FUND: National Institute of Allergy and Infectious Diseases

A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension

Copyright The Author(s) 2016. This article is published with open access at Springerlink.com. Open Access - This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were madePulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.Peer reviewedFinal Published versio

Uncertainty in hydrological signatures for gauged and ungauged catchments

Reliable information about hydrological behavior is needed for water‐resource management and scientific investigations. Hydrological signatures quantify catchment behavior as index values, and can be predicted for ungauged catchments using a regionalization procedure. The prediction reliability is affected by data uncertainties for the gauged catchments used in prediction and by uncertainties in the regionalization procedure. We quantified signature uncertainty stemming from discharge data uncertainty for 43 UK catchments and propagated these uncertainties in signature regionalization, while accounting for regionalization uncertainty with a weighted‐pooling‐group approach. Discharge uncertainty was estimated using Monte Carlo sampling of multiple feasible rating curves. For each sampled rating curve, a discharge time series was calculated and used in deriving the gauged signature uncertainty distribution. We found that the gauged uncertainty varied with signature type, local measurement conditions and catchment behavior, with the highest uncertainties (median relative uncertainty ±30–40% across all catchments) for signatures measuring high‐ and low‐flow magnitude and dynamics. Our regionalization method allowed assessing the role and relative magnitudes of the gauged and regionalized uncertainty sources in shaping the signature uncertainty distributions predicted for catchments treated as ungauged. We found that (1) if the gauged uncertainties were neglected there was a clear risk of overconditioning the regionalization inference, e.g., by attributing catchment differences resulting from gauged uncertainty to differences in catchment behavior, and (2) uncertainty in the regionalization results was lower for signatures measuring flow distribution (e.g., mean flow) than flow dynamics (e.g., autocorrelation), and for average flows (and then high flows) compared to low flows.Key Points:We quantify impact of data uncertainty on signatures and their regionalizationMedian signature uncertainty ±10–40%, and highly variable across catchmentsNeglecting gauging uncertainty causes overconditioning of regionalizationPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/1/wrcr21917-sup-0001-2015WR017635-s01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/2/wrcr21917.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/3/wrcr21917_am.pd

Parental influences on children's eating behaviour and characteristics of successful parent-focussed interventions

Parental reports suggest that difficulties related to child-feeding and children's eating behaviour are extremely common. While 'fussy eating' does not pose an immediate threat to health, over the long-term, consumption of a poor diet can contribute to the development of a range of otherwise preventable diseases. In addition, the stress and anxiety that can surround difficult mealtimes can have a detrimental impact upon both child and parental psychological wellbeing. Since parents have a great influence over what, when, and how much food is offered, feeding difficulties may be preventable by better parental awareness. The aim of this review is to describe how parental factors contribute to the development of common feeding problems, and to discuss the merits of existing interventions aimed at parents/primary caregivers to improve child-feeding and children's eating behaviour. The potential for different technologies to be harnessed in order to deliver interventions in new ways will also be discussed

The Lancaster Care Charter

In the fall of 1991 the Munich Design Charter was published in Design Issues. This charter was written as a design-led “call to arms” on the future nations and boundaries of Europe. The signatories of the Munich Design Charter saw the problem of Europe, at that time, as fundamentally a problem of form that should draw on the creativity and expertise of design. Likewise, the Does Design Care…? workshop held at Imagination, Lancaster University in the autumn of 2017 brought together a multidisciplinary group of people from 16 nations across 5 continents, who, at a critical moment in design discourse saw a problem with the future of Care. The Lancaster Care Charter has been written in response to the vital question “Does Design Care…?” and via a series of conversations, stimulated by a range of presentations that explored a range of provocations, insights, and more questions, provides answers for the contemporary context of Care. With nation and boundary now erased by the flow of Capital the Charter aims to address the complex and urgent challenges for Care as both the future possible and the responsibility of design. The Lancaster Care Charter presents a collective vision and sets out new pragmatic encounters for the design of Care and the care of Design

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca's 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year