Search

Objective For cost-effectiveness comparison of child vision and hearing screening programmes, methods and data should be available. We assessed the current state of data collection and its availability in Europe. Methods The EUSCREEN Questionnaire, conducted in 2017–2018, assessed paediatric vision and hearing screening programmes in 45 countries in Europe. For the current study, its items on data collection, monitoring and evaluation, and six of eleven items essential for cost-effectiveness analysis: prevalence, sensitivity, specificity, coverage, attendance and loss to follow-up, were reappraised with an additional questionnaire. Results The practice of data collection in vision screening was reported in 36% (N = 42) of countries and in hearing screening in 81% (N = 43); collected data were published in 12% and 35%, respectively. Procedures for quality assurance in vision screening were reported in 19% and in hearing screening in 26%, research of screening effectiveness in 43% and 47%, whereas cost-effectiveness analysis was performed in 12% for both. Data on prevalence of amblyopia were reported in 40% and of hearing loss in 77%, on sensitivity of screening tests in 17% and 14%, on their specificity in 19% and 21%, on coverage of screening in 40% and 84%, on attendance in 21% and 37%, and on loss to follow-up in 12% and 40%, respectively. Conclusions Data collection is insufficient in hearing screening and even more so in vision screening: data essential for cost-effectiveness comparison could not be reported from most countries. When collection takes place, this is mostly at a local level for quality assurance or accountability, and data are often not accessible. The resulting inability to compare cost-effectiveness among screening programmes perpetuates their diversity and inefficiency.

Over the past ten years, the Psychologically Informed Environments (PIEs) framework has become a popular approach to service delivery and practice with people experiencing homelessness. However, there is a dearth of evidence supporting the implementation of this framework, despite anecdotal reports of its utility and effectiveness. This mixed methods systematic review aims to answer the following three questions: 1) What interventions aimed at staff have been used to implement PIE principles in homelessness services? 2) What is the impact of implementing PIE interventions with staff working in homelessness services? 3) What are the barriers and facilitators to implementing PIE approaches in homelessness services?

A diagnosis of cancer in childhood or adolescence has an significant impact on school attendance, educational experience and outcomes. We plan to conduct a scoping review to identify what is known from the existing literature about access to and experience of education for children and adolescents with cancer during and after treatment. We will utilise the six steps outlined by Arksey and O'Malley (2005) including the use of a consultation exercise with healthcare and educational professionals, patients and their families.

Purpose Nystagmus is a disorder characterized by uncontrolled, rhythmic oscillations of the eyes. It often causes reduced visual function beyond reduced visual acuity alone. There is a paucity of literature regarding the public understanding of nystagmus, and there are no published data on the impact of the COVID-19 pandemic on people living with the condition. This study explores the self-reported impact of the COVID-19 pandemic on those with nystagmus, and examines both public understanding of how nystagmus affects people who have it and the perceptions of public understanding by those with the condition and their carers. Methods A qualitative questionnaire was designed following a stakeholder engagement process. This questionnaire was advertised via social media platforms and charity websites to achieve widespread recruitment. Data were collected between November and December 2020. Participants were divided into two groups based on their response to the question: “Do you, or anyone you know well, have nystagmus?”. Questions were posed to participants in a purpose-built, branching survey. The resulting data were analyzed using descriptive and inferential statistical methods. Results One thousand six hundred forty-five respondents were recruited, of which 849 (51.6%) answered “Yes” to the initial filtering question. Analysis showed that, broadly, public understanding of nystagmus differs from the perception of it by those with nystagmus and their carers, that the COVID-19 pandemic has had a significant impact on those with nystagmus, and that respondents who have met someone with nystagmus, even briefly, tend to have a greater understanding of the impact of the condition. Conclusion This study highlights the lack of public awareness regarding nystagmus and suggests opportunities to increase the awareness of nystagmus without the need for extensive knowledge of the condition. The COVID-19 pandemic has posed additional difficulties for those living with nystagmus, which is likely to be comparable among those with similar ocular disorders.

To describe and compare vision screening programmes and identify variance in number and type of tests used, timing of screening, personnel involved, monitoring and funding to be used as data for optimising, disinvesting or implementing future screening programmes. A questionnaire consisting of nine domains: demography & epidemiology, administration & general background, existing screening, coverage & attendance, tests, follow-up & diagnosis, treatment, cost & benefit and adverse effects was completed by Country Representatives (CRs) recruited from 47 countries. The questionnaire was sufficiently completed for 46 Countries: 42 European countries, China, India, Malawi and Rwanda. Variation of provision was found in; age of screening (0-17 years), tests included (23), types of visual acuity (VA) test used (35 different optotypes), personnel (13), number of screens per child (median 5, range 1-32), and times VA tested (median 3, range 1-30). Infant screening is offered in all countries, whereas childhood vision screening is offered at least once in all countries, but not all regions of each country. All 46 countries provide vision screening between the ages of 3-7 years. Data on screening outcomes for quality assurance was not available from most countries; complete evaluation data was available in 2% of countries, partial data from 43%. Vision screening is highly variable. Some form of VA testing is being undertaken during childhood. Data collection and sharing should be improved to facilitate comparison and to be able to optimise vision screening programmes between regions and countries.

Supplemental material, sj-docx-1-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-4-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-1-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-4-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-3-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-3-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-2-msc-10.1177_09691413221126677 for Availability of data for cost-effectiveness comparison of child vision and hearing screening programmes by Jan Kik, Eveline A.M. Heijnsdijk, Allison R. Mackey, Gwen Carr, Anna M Horwood, Maria Fronius, Jill Carlton, Helen J Griffiths, Inger M Uhlén, Huibert Jan Simonsz and Country-Committees Joint-Partnership of the EUSCREEN Study Consortium in Journal of Medical Screening

Supplemental material, sj-docx-1-joo-10.1177_14653125211029959 for Patient reported experiences and treatment outcomes of orthodontic patients treated within secondary care settings in the South West of England during the COVID-19 pandemic by Jenifer L Jopson, Pamela E Ellis, Amelia S Jerreat, Louise C Kneafsey, Matthew B Moore, Christian Day, Julia K Scott, Helen Griffiths, Tara VN Lee, Graham R Oliver, Peter V Fowler, Martyn Sherriff and Anthony J Ireland in Journal of Orthodontics

Additional file 1. PRISMA-P 2015 Checklist. A completed PRISMA-P checklist for the scoping review.

Vision screening in school has long been regarded as an effective way to reduce the prevalence rate of amblyopia induced by strabismus, high refractive error or other causes (Vision in preschool study group, 2003, Solebo, Cumberland & Rahi, 2014, Tailor et al, 2016). Early vision screening can detect the presence of amblyopia whilst it can still be treated, therefore preventing serious permanent visual loss in an early stage of life (Powell and Hatt, 2009). Despite the importance of early detection of amblyopia being indisputable, the format of vision screening varies. The UK National Screening Committee (NSC), based on available evidence (Hall and Elliman, 2003), recommended that children aged 4-5 should receive vision screening (UKNSC, 2019). In 2017, a service specification was published by Public Health England (PHE) to guide local authorities (LA) in commissioning vision screening services (PHE, 2017). The specification provided detailed guidance on the evidence-based practice in providing vision screening services. The PHE specification recommended that the service should be orthoptist led; children with best corrected VA less than 0.200 logMAR, measured by Keeler crowded logMAR test, should be referred. Despite the detailed guidance provided by PHE, the level of adherence ofLA in commissioning vision screening has not yet been revealed.The British and Irish Orthoptics Society (BIOS) Vision Screening Clinical Advisory Group (CAG) is working to improve the quality of vision screening and to ensure best practice across the country. Hence it is paramount to promote the importance of the PHE guideline and to investigate the potential effect it brings. In addition, the 2018-2019 vision screening audit aims at mappingout current practices of vision screening across the UK and Ireland, identify changes in practice from the previous year and the effect of various factors on the effectiveness of vision screening. The intention is for this audit can facilitate the benchmarking of services and provide evidence toaid orthoptists and LAs in making informed decisions regarding vision screening commissioning.

Additional file 2. Draft Search Strategy for Medline. A draft search strategy to be used in the Medline database.

Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5’-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1–20μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20μM POVPC. Following delivery of lutein (0.1-1μM) and zeaxanthin (0.5-5μM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was > 50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1μM but not 20μM POVPC, whereas the increase in ROS production induced by 20μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20μM but not 1μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids.

Additional file 4.

Additional file 3: Supplementary Table S1- WHO Trial registry dataset.

Additional file 2. Consent Form.

Additional file 1. Patient Information pack.

Although advances have been made in the understanding and treatment of positive symptoms of psychosis such as paranoid thinking and voice-hearing, negative symptoms such as loss of motivation and reduced social functioning often present a major barrier to recovery. The psychosocial treatment options for negative symptoms should benefit from systematic examination and refinement, both in terms of the models used to understand symptom development and maintenance as well as the specific treatment techniques. We examine the possibility that negative symptom burden is particularly related to insecure-avoidant attachment style and that this manifests in difficulties with understanding one’s own mental states and the minds of others. Drawing on key studies that have examined mentalisation and related processes alongside negative symptom profile data, we provide a model of negative symptom formation and maintenance along with a case example that portrays the use of these principles in case formulation and treatment.

Background:\ud \ud Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population.\ud Objectives:\ud \ud To evaluate the clinical effectiveness and cost-effectiveness of cognitive–behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome.\ud Design:\ud \ud The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU).\ud Setting:\ud \ud Secondary care mental health services in five cities in the UK.\ud Participants:\ud \ud People with CRS aged up to 16 years, with an International Classification of Diseases, Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms.\ud Interventions:\ud \ud Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services.\ud Main outcome measures:\ud \ud The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs.\ud Results:\ud \ud Participants were allocated to CBT (n = 242) or TAU (n = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) –3.32 to 1.55 points; p = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (–2.40 points, 95% CI –4.79 to –0.02 points; p = 0.049). CBT was associated with a net cost of £5378 (95% CI –£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability

Aim: This audit utilises data submitted by Head Orthoptists to the British and Irish Orthoptic Society (BIOS). The aim is to describe vision screening practices across the United Kingdom (UK) for the academic year 2017-2018, compare the findings to the previous audits for academic years 2015-2016 and 2016-2017, and to provide evidence for future decision-making. Method: An Excel spreadsheet and guidance for completion was sent to 204 Orthoptic Heads of Service for submission in March 2019. Submitted data was integrated and the information was analysed to identify types of provision and outcomes across sites. Results: Twenty-eight sites (13.7%) responded to the data request, or these twenty-seven provided basic site data including consent policy and age at which tests are performed; a decrease from the previous academic years 2015-2016 (n=52 sites) and 2016-2017 (n=50 sites). Twenty-seven sites provided data on which professional administered screening, the test(s) used and the pass criteria adopted. These twenty-seven sites provided data regarding the referral pathway and twenty-five sites provided data on diagnostic examination and management criteria. Twenty-five sites provided data regarding the number of children screened (n=114,831), of which fifteen sites provided complete ‘accurate’ data on the number of children who failed screening (n=7,060 out of 65,959 screened). These twenty-five sites provided ‘accurate’ data on the number of children who attended their diagnostic follow-up (n=8,569). Eleven sites (n=4,645 children seen) provided data on initial outcomes of the eye examination and sixteen sites (n=2,366 children seen) provided diagnostic test data. The mean coverage increased to 98.3% (2016-2017=93%, 2015-16 =89%). True +ve rates were difficult to compare for each profession delivering screening, because of small numbers of submission with varied practice of test used, referral criteria and number of screens offered to each child. Mean True +ve rates where a second screen was provided in school for children with borderline fail VA were 90% compared to a mean of 71% in sites where no 2nd screen was performed. Improved True +ve rates were also evident in sites who provided a second screen if the child was unable to perform the test. In both instances data relating to the second screening outcomes were limited and require further analysis. Conclusions: This audit concludes that many screening services do not have reliable methods to collect data to assess the effectiveness of the programme. A more effective method for collecting data and consistency in reporting is required to allow comparison and benchmarking of services. Without this, it is not possible to definitively conclude the effectiveness of vision screening, whether the professional delivering screening and type of vision screener training influences True +ve rates. The current limited data suggests that a second screen of children with borderline fail results or unable to perform the test reduces false positive referrals; cost-benefit analysis is required. The implications of these points are discussed.

Background: Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30–40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.\ud Methods: We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised- permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.\ud Findings: From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference –0·89, 95% CI –3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference –2·40, –4·79 to –0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (

BackgroundAlthough clozapine is the treatment of choice for treatment-refractory schizophrenia, 30–40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.MethodsWe did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.FindingsFrom Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference −0·89, 95% CI −3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference −2·40, −4·79 to −0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (

Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25S-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25S-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date. We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72-82 % and sensitivities between 5-135ng. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia. Twenty healthy male volunteers were recruited (aged 41-63 years); ten were asymptomatic with high plasma cholesterol >6.5mM and ten were healthy with normal plasma cholesterol (

Aim: This audit utilises data submitted by Head Orthoptists to the British and Irish Orthoptic Society (BIOS). The aim is to attempt to describe vision screening practices across the United Kingdom (UK) for the academic year 2016-2017, compare the findings to the previous vision screening audit for academic year 2015-2016 and provide evidence for future decision-making. Method: Submitted data was integrated into an Excel spreadsheet and the information was analysed to identify the differences between screening programmes across sites. The method of calculating True +ve scores was explored using three methods (as explained in 2015-2016 audit) and the effects of training on True +ve are discussed. Data was deemed ‘accurate’, such as at the analysis of initial outcomes, only if all children seen after referral were accounted for in the initial outcomes section. Results: Fifty sites provided basic data including consent policy and age at which tests are performed; a decrease from the previous academic year 2015-2016 (n=52 sites). Forty-three sites provided data on which professional administered the tests, the test(s) used and the pass criteria adopted. Forty-one sites provided data regarding the referral pathway and forty-three sites provided data on eye exam and management criteria. Forty-two sites provided data regarding the number of children screened (n=162,868), of which thirty sites provided ‘accurate’ data on the number of children who failed screening (n=15,383). Thirty-eight sites provided ‘accurate’ data on the number of children who attended their follow-up (n=10,748). Eighteen sites (n=4,645 children seen) provided data on initial outcomes of the eye examination and sixteen sites (n=4,060 children seen) provided diagnostic test data on the number of True positives (+ve). The mean coverage increased to 93% (2016-2016=89%). Using Method 1 of calculating True +ve: Orthoptic delivered screening (n=1,790) showed a mean True +ve of 89%; Vision Screener (VS) trained by an Orthoptist using the BIOS package (n=608) showed a mean True +ve of 81%; VS trained by an Orthoptist using a local package (n=804) showed a mean True +ve of 71%; and VS not trained by an Orthoptist (n=126) showed a mean True +ve of 59%. Conclusions: This audit concludes that many screening services do not have methods to collect data to assess the effectiveness of the programme. Clarity is needed regarding the meaning of certain terms to achieve consistency in reporting and allow comparison and benchmarking of services, for example, in recording True+ve. Without this, it is not possible to definitively conclude whether professional delivering screening and type of vision screener training does influence True +ve rates or not. The current limited data suggests that the training received/professional administering the test affects the number of True +ve. The implications are discussed.

Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease.

Summary Differences in lipid metabolism associate with age‐related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro‐inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age‐associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly‐ and mono‐unsaturated FAs increase with age. Circulating TNF‐α and IL‐6 concentrations increased with age, whereas IL‐10 and TGF‐β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF‐β1 concentrations, and higher C16:0 were associated with higher TNF‐α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro‐inflammatory cytokines in response to phorbol myristate acetate‐induced differentiation through ceramide‐dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro‐resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti‐inflammatory macrophages through metabolic reprogramming.

Aim: This audit utilises data submitted by Head Orthoptists to the British and Irish Orthoptic Society (BIOS). The aim is to provide insights into vision screening practices across the United Kingdom (UK) for the academic year 2015-2016, compare the findings to the previous vision screening audit for academic year 2014-2015 and provide evidence for future decision making regarding best practice. Method: Fifty-nine sites provided data with four instances of site amalgamation. Site representatives were contacted to confirm new area details, duplicated submissions were identified and one submission in each case was used in the analysis. Fifty-two sites remained (number of children screened (n) = 168,239). Thirty-eight sites (n=148,159) provided further screening outcome data. Of these, twenty sites (n=6,101) provided further diagnostic test data on the number of true positives (+ve). The method of calculating True +ve scores was explored and the implications discussed.Results: The number of sites participating in the current BIOS vision screening audit for academic year 2015-2016 increased from the previous academic year (2014-2015) from 56 to 59. This number of 59 reduces to 52 when combined data and duplicated submissions were accounted for. The mean coverage decreased from 91% in the academic year 2014-2015 to 89% in the current audit of academic year 2015-2016.Calculation of mean true +ve for the sites was conducted using three separate methods. Whilst noting methods 1 and 2, this audit focuses on method 3 for interpretation. Sites providing Orthoptic delivered screening (n=3123) showed a mean true +ve of 79%, Vision Screener trained by an Orthoptist using the BIOS package (n=889) showed a mean True +ve of 66%, Vision Screener trained by an Orthoptist using a local package (n= 1452) showed a mean True +ve of 66%, and Vision Screener not trained by an Orthoptist (n=637) showed mean True +ve of 41%.Conclusions: This audit concludes that there is a need for further investigation into the effects of training received on True +ve scores. It suggests that the level of training received/professional administering the test affects the number of True +ve. The implications are discussed.

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.

The present document describes a nutritional approach that is nested in the European Innovation Partnership for Active and Healthy Aging (EIP-AHA) and aims to provide the first common European program translating an integrated approach to nutritional frailty in terms of a multidimensional and transnational methodology. The document has been developed by the A3 Nutrition Action Area of the EIP-AHA and aims at providing a stepwise approach to malnutrition in older citizens, identifying adequate interventions based on a unified assessment and ICT-supported solutions. “NutriLive” is an integrated nutritional approach, represented by a structured Screening-Assessment-Monitoring-Action-Pyramid-Model (SAM-AP). Its core concept is the stratification of the nutritional needs, considered by the working group as the key for targeted, effective, and sustainable interventions. “NutriLive” tries to close gaps in epidemiological data within an aging population, creating a unified language to deal with the topic of nutrition and malnutrition in Europe. By assembling all the validated screening, assessment, and monitoring tools on malnutrition in a first pyramid, which is interrelated to a second intervention pyramid, the A3 Nutrition WG identifies a common, integrated vision on the nutritional approach to frailty, which applies to the various health care settings.

Purpose Primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss. Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved. We analyzed carefully characterized POAG cases in a genome-wide association study (GWAS). Methods We performed a GWAS in 387 POAG cases using public control data (WTCCC2). We also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP). Promising single nucleotide polymorphisms (SNPs), based on various prioritisation criteria, were genotyped in a cohort of 294 further POAG cases and controls. Results We found 2 GWAS significant results in the discovery stage for association, one of which which had multiple evidence in the gene ‘neural precursor cell expressed, developmentally down-regulated 9’ (NEDD9; rs11961171, p=8.55E-13) and the second on chromosome 16 with no supporting evidence. Taking into account all the evidence from risk and quantitative trait ocular phenotypes we chose 86 SNPs for replication in an independent sample. Our most significant SNP was not replicated (p=0.59). We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing. Two of these, for phenotypes CDR (rs4385494, discovery p=4.51x10–5, replication p=0.029) and CCT (rs17128941, discovery p=5.52x10–6, replication=0.027), show the consistent direction of effects between the discovery and replication data. We also assess evidence for previously associated known genes and find evidence for the genes ‘transmembrane and coiled-coil domains 1’ (TMCO1) and ‘cyclin-dependent kinase inhibitor 2B’ (CDKN2B). Conclusions Although we were unable to replicate any novel results for POAG risk, we did replicate two SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing. There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits. We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study. Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.

Elevated LDL concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidative modification (oxLDL) and nitration is observed during dementia and hypercholesterolemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVEC) were maintained on transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naïve, normo- and hyperlipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40mg simvastatin intervention/day for three months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after three months. LDL isolated from statin-naïve hyperlipidaemic, AD and AD-plus subjects was more oxidised (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared to control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 Vs 3.95±0.2nmol/mg; P

Prophylactic vaccines are an effective strategy to prevent development of many infectious diseases. With new and re-emerging infections posing increasing risks to food stocks and the health of the population in general, there is a need to improve the rationale of vaccine development. One key challenge lies in development of an effective T cell-induced response to subunit vaccines at specific sites and in different populations. Objectives: In this review, we consider how a proteomic systems-based approach can be used to identify putative novel vaccine targets, may be adopted to characterise subunit vaccines and adjuvants fully. Key findings: Despite the extensive potential for proteomics to aid our understanding of subunit vaccine nature, little work has been reported on identifying MHC 1-binding peptides for subunit vaccines generating T cell responses in the literature to date. Summary: In combination with predictive and structural biology approaches to mapping antigen presentation, proteomics offers a powerful and as yet un-tapped addition to the armoury of vaccine discovery to predict T-cell subset responses and improve vaccine design strategies.

Objective To examine the diversity in paediatric vision and hearing screening programmes in Europe. Methods Themes for comparison of screening programmes derived from literature were used to compile three questionnaires on vision, hearing, and public health screening. Tests used, professions involved, age, and frequency of testing seem to influence sensitivity, specificity, and costs most. Questionnaires were sent to ophthalmologists, orthoptists, otolaryngologists, and audiologists involved in paediatric screening in all EU full-member, candidate, and associate states. Answers were cross-checked. Results Thirty-nine countries participated; 35 have a vision screening programme, 33 a nation-wide neonatal hearing screening programme. Visual acuity (VA) is measured in 35 countries, in 71% of these more than once. First measurement of VA varies from three to seven years of age, but is usually before age five. At age three and four, picture charts, including Lea Hyvarinen, are used most; in children over four, Tumbling-E and Snellen. As first hearing screening test, otoacoustic emission is used most in healthy neonates, and auditory brainstem response in premature newborns. The majority of hearing testing programmes are staged; children are referred after 1–4 abnormal tests. Vision screening is performed mostly by paediatricians, ophthalmologists, or nurses. Funding is mostly by health insurance or state. Coverage was reported as >95% in half of countries, but reporting was often not first-hand. Conclusion Largest differences were found in VA charts used (12), professions involved in vision screening (10), number of hearing screening tests before referral (1–4), and funding sources (8).

Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4 μg oxLDL and 25 μM 27-hydroxycholesterol (27OH-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. © 2014 The Authors.

Blood cholesterol levels are not consistently elevated in subjectswith age-related cognitive decline, although epidemiological studies suggest that Alzheimer's disease and cardiovascular diseases share common risk factors. These include the presence of an unusual genetic variant, the APOE4 (apolipoprotein E4) allele, which modulates LDL (low-density lipoproteins) metabolism, increases free radical formation and reduces plasma antioxidant concentrations. Together, these risk factors support a mechanism for increased LDL circulation time and free radical modification of LDL. Plasma oxycholesterols, hydroxylated metabolites of cholesterol, are carried by oxidized LDL, and elevated lipids in mid-life are associated with increased longterm risk of dementia. Although brain cholesterol metabolism is segregated from the systemic circulation, during oxidative stress, plasma oxycholesterols could have damaging effects on BBB (blood-brain barrier) function and consequently on neuronal cells. Cholesterol-lowering drugs such as statins may prevent the modifications to LDL in mid-life and might show beneficial effects in later life. © The Authors Journal compilation © 2014 Biochemical Society.

Background - Plants have proved to be an important source of anti-cancer drugs. Here we have investigated the cytotoxic action of an aqueous extract of Fagonia cretica, used widely as a herbal tea-based treatment for breast cancer. Methodology/Principal Findings - Using flow cytometric analysis of cells labeled with cyclin A, annexin V and propidium iodide, we describe a time and dose-dependent arrest of the cell cycle in G0/G1 phase of the cell cycle and apoptosis following extract treatment in MCF-7 (WT-p53) and MDA-MB-231 (mutant-p53) human breast cancer cell lines with a markedly reduced effect on primary human mammary epithelial cells. Analysis of p53 protein expression and of its downstream transcription targets, p21 and BAX, revealed a p53 associated growth arrest within 5 hours of extract treatment and apoptosis within 24 hours. DNA double strand breaks measured as ?-H2AX were detected early in both MCF-7 and MDA-MB-231 cells. However, loss of cell viability was only partly due to a p53-driven response; as MDA-MB-231 and p53-knockdown MCF-7 cells both underwent cell cycle arrest and death following extract treatment. p53-independent growth arrest and cytotoxicity following DNA damage has been previously ascribed to FOXO3a expression. Here, in MCF-7 and MDA-MB-231 cells, FOXO3a expression was increased significantly within 3 hours of extract treatment and FOXO3 siRNA reduced the extract-induced loss of cell viability in both cell lines. Conclusions/Significance - Our results demonstrate for the first time that an aqueous extract of Fagonia cretica can induce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response. We also show that FOXO3a is required for activity in the absence of p53. Our findings indicate that Fagonia cretica aqueous extract contains potential anti-cancer agents acting either singly or in combination against breast cancer cell proliferation via DNA damage-induced FOXO3a and p53 expression.

PURPOSE: To evaluate whether Chlamydia (C.) infections are associated with age-related macular degeneration (AMD) and to assess if this association is influenced by the complement factor H (CFH) Y402H or the high temperature requirement A serine peptidase 1 (HTRA1) rs11200638 risk genotypes.METHODS: One hundred ninety-nine AMD patients with early and late forms of the disease and 100 unaffected controls, at least 50 years old were included in the study. Patients in the AMD and control groups were selected based on known CFH Y402H variant genotype status (one third homozygous CC, one third heterozygous CT, and one third wild-type TT). Plasma from all patients and controls was tested for C. pneumoniae, C. trachomatis, and C. psittaci IgG seropositivity using a micro-immunofluorescent assay to establish previous infection status. Assays were conducted blind to risk genotypes and the results analyzed using univariate and multivariate (logistic regression) analysis.RESULTS:IgG seropositivity to C. pneumoniae was most prevalent (69.2%, n=207), followed by C. trachomatis (7.4%, n=22) and C. psittaci (3.3%, n=10). No association was found between each of the three Chlamydia species IgG seropositivity and AMD status or severity (early/late). There was also no significant association between Chlamydia species IgG seropositivity and AMD status or severity, in patients carrying at least one CFH Y402H risk allele (C) or HTRA1 rs11200638 risk allele (A), with univariate or logistic regression analysis. CONCLUSIONS:Chlamydia infection status does not appear to be associated with AMD status or severity. The presence of CFH Y402H and HTRA1 rs11200638 risk genotypes does not alter this negative association.

Introduction - Rheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality, attributed to both traditional and novel cardiovascular risk factors. The metabolic syndrome, a cluster of classical cardiovascular risk factors, including hypertension, obesity, glucose intolerance, and dyslipidaemia, is highly prevalent in RA. Reports suggest that long-term glucocorticoid (GC) use may exacerbate individual cardiovascular risk factors, but there have been no studies in RA to assess whether it associates with the metabolic syndrome. We examined whether GC exposure associates with the presence of metabolic syndrome in patients with RA. Methods - RA patients (n = 398) with detailed clinical and laboratory assessments were categorised into three groups according to GC exposure: no/limited (

Porphyromonas gingivalis, a gram-negative anaerobe which is implicated in the etiology of active periodontitis, secretes degradative enzymes (gingipains) and sheds proinflammatory mediators (e.g., lipopolysaccharides [LPS]). LPS triggers the secretion of interleukin-8 (IL-8) from immune (72-amino-acid [aa] variant [IL-8(72aa)]) and nonimmune (IL-8(77aa)) cells. IL-8(77aa) has low chemotactic and respiratory burst-inducing activity but is susceptible to cleavage by gingipains. This study shows that both R- and K-gingipain treatments of IL-8(77aa) significantly enhance burst activation by fMLP and chemotactic activity (P < 0.05) but decrease burst activation and chemotactic activity of IL-8(72aa) toward neutrophil-like HL60 cells and primary neutrophils (P < 0.05). Using tandem mass spectrometry, we have demonstrated that R-gingipain cleaves 5- and 11-aa peptides from the N-terminal portion of IL-8(77aa) and the resultant peptides are biologically active, while K-gingipain removes an 8-aa N-terminal peptide yielding a 69-aa isoform of IL-8 that shows enhanced biological activity. During periodontitis, secreted gingipains may differentially affect neutrophil chemotaxis and activation in response to IL-8 according to the cellular source of the chemokine.

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of β-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature - vascular or degenerative - dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development. Copyright © 2004 S. Karger AG, Basel.

The cultivated potato (Solanum tuberosum) shares similar biology with other members of the Solanaceae, yet has features unique within the family, such as modified stems (stolons) that develop into edible tubers. To better understand potato biology, we have undertaken a survey of the potato transcriptome using expressed sequence tags (ESTs) from diverse tissues. A total of 61,940 ESTs were generated from aerial tissues, below-ground tissues, and tissues challenged with the late-blight pathogen (Phytophthora infestans). Clustering and assembly of these ESTs resulted in a total of 19,892 unique sequences with 8,741 tentative consensus sequences and 11,151 singleton ESTs. We were able to identify a putative function for 43.7% of these sequences. A number of sequences (48) were expressed throughout the libraries sampled, representing constitutively expressed sequences. Other sequences (13,068, 21%) were uniquely expressed and were detected only in a single library. Using hierarchal and k means clustering of the EST sequences, we were able to correlate changes in gene expression with major physiological events in potato biology. Using pair-wise comparisons of tuber-related tissues, we were able to associate genes with tuber initiation, dormancy, and sprouting. We also were able to identify a number of characterized as well as novel sequences that were unique to the incompatible interaction of late-blight pathogen, thereby providing a foundation for further understanding the mechanism of resistance.

Proteins are susceptible to oxidation by reactive oxygen species, where the type of damage induced is characteristic of the denaturing species. The induction of protein carbonyls is a widely applied biomarker, arising from primary oxidative insult. However, when applied to complex biological and pathological conditions it can be subject to interference from lipid, carbohydrate and DNA oxidation products. More recently, interest has focused on the analysis of specific protein bound oxidised amino acids. Of the 22 amino acids, aromatic and sulphydryl containing residues have been regarded as being particularly susceptible to oxidative modification, with L-DOPA from tyrosine, ortho-tyrosine from phenylalanine; sulphoxides and disulphides from methionine and cysteine respectively; and kynurenines from tryptophan. Latterly, the identification of valine and leucine hydroxides, reduced from hydroperoxide intermediates, has been described and applied. In order to examine the nature of oxidative damage and protective efficacy of antioxidants the markers must be thoroughly evaluated for dosimetry in vitro following damage by specific radical species. Antioxidant protection against formation of the biomarker should be demonstrated in vitro. Quantification of biomarkers in proteins from normal subjects should be within the limits of detection of any analytical procedure. Further to this, the techniques for isolation and hydrolysis of specific proteins should demonstrate that in vitro oxidation is minimised. There is a need for the development of standards for quality assurance material to standardise procedures between laboratories. At present, antioxidant effects on protein oxidation in vivo are limited to animal studies, where dietary antioxidants have been reported to reduce dityrosine formation during rat exercise training. Two studies on humans have been reported last year. The further application of these methods to human studies is indicated, where the quality of the determinations will be enhanced through inter-laboratory validation.

Over the past forty years the transnational women’s movement has worked to conceptualise and institutionalise the understanding of violence against women as a gendered human rights violation. Their efforts have led the response at the international level, and have shaped the (markedly feminist) international human rights law approach to violence against women.\ud \ud Despite successes in conceptualising and institutionalising norms concerning the elimination of violence against women, there remain problems in implementing these norms and holding states accountable. As such, violence against women is still pandemic, affecting at least one in three women. An area worthy of additional research and attention is state responsibility for prevention – particularly primary prevention, aimed at the ‘upstream’ or ‘root’ causes of violence against women – and the use of the due diligence standard as a tool for actualising this obligation. The due diligence standard is a significant development of state responsibility, which, within the context of human rights protection, broadens notions of state responsibility to include instances where there is a failure to exercise due care to prevent or respond to violative acts or omissions of private or non-state actors. In the context of violence against women, this provides a ‘juridical bridge’ for addressing private violence, particularly domestic violence, as a human rights violation, for which the state can – and should – be held accountable. The evolution of ‘systemic due diligence’ – aimed at the broader level of human rights protection – has furthered this feminist theory of state responsibility.\ud \ud The aim of this thesis is to deepen the understanding of violence against women as a gendered human rights violation and to discover how the due diligence standard can be better used as a tool to bring about its elimination; if, indeed, it is fit for this purpose.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.