The impacts of tourism on two communities adjacent to the Kruger National Park, South Africa

This paper explores the socioeconomic impacts of tourism associated with the Kruger National Park, South Africa's flagship national park, on the neighbouring villages of Cork and Belfast. Case study research, where the study area was characterised as a social-ecological system, was used to investigate the impacts of Park tourism on these communities. The findings offer a micro-scale, local community perspective of these impacts and indicate that the enclave nature of Park tourism keeps local communities separate from the Park and makes it hard for them to benefit from it. The paper concludes with reflections on this perceived separation, and suggests the need to make the Park boundaries more 'permeable' so as to improve relationships with adjacent communities, while also pragmatically managing community expectation

Vitamin D and the risk of treatment-resistant and atypical depression: A Mendelian randomization study

Observational evidence has implicated vitamin D levels as a risk factor in major depressive disorder (MDD). Confounding or reverse causation may be driving these observed associations, with studies using genetics indicating little evidence of an effect. However, genetic studies have relied on broad definitions of depression. The genetic architecture of different depression subtypes may vary since MDD is a highly heterogenous condition, implying potentially diverging requirements in therapeutic approaches. We explored the associations between vitamin D and two subtypes of MDD, for which evidence of a causal link could have the greatest clinical benefits: treatment-resistant depression (TRD) and atypical depression (AD). We used a dual approach, combining observational data with genetic evidence from polygenic risk scores (PRS) and two-sample Mendelian randomization (MR), in the UK Biobank. There was some evidence of a weak association between vitamin D and both incident TRD (Ncases = 830) and AD (Ncases = 2366) in observational analyses, which largely attenuated when adjusting for confounders. Genetic evidence from PRS and two-sample MR, did not support a causal link between vitamin D and either TRD (Ncases = 1891, OR = 1.01 [95%CI 0.78, 1.31]) or AD (Ncases = 2101, OR = 1.04 [95%CI 0.80, 1.36]). Our comprehensive investigations indicated some evidence of an association between vitamin D and TRD/AD observationally, but little evidence of association when using PRS and MR, mirroring findings of genetic studies of vitamin D on broad depression phenotypes. Results do not support further clinical trials of vitamin D in these MDD subtypes but do not rule out that small effects may exist that require larger samples to detect

Report for the EcoNomics of Adaptive Clinical Trials (ENACT) project : Application of a Bayesian Value-Based Sequential Model of a Clinical Trial to the CACTUS and HERO Case Studies (with Guidance Material for Clinical Trials Units)

none8siNo abstract.openM. Forster, L. Flight, B. Corbacho, A. Keding, S. Ronaldson, P. Tharmanathan, A. Brennan, S. ChickM. Forster, L. Flight, B. Corbacho, A. Keding, S. Ronaldson, P. Tharmanathan, A. Brennan, S. Chic

Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment

Background Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. Methods To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). Results [3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. Conclusions The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-κβ and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site

HIV-1 gp120 Induces Expression of IL-6 through a Nuclear Factor-Kappa B-Dependent Mechanism: Suppression by gp120 Specific Small Interfering RNA

In addition to its role in virus entry, HIV-1 gp120 has also been implicated in HIV-associated neurocognitive disorders. However, the mechanism(s) responsible for gp120-mediated neuroinflammation remain undefined. In view of increased levels of IL-6 in HIV-positive individuals with neurological manifestations, we sought to address whether gp120 is involved in IL-6 over-expression in astrocytes. Transfection of a human astrocyte cell line with a plasmid encoding gp120 resulted in increased expression of IL-6 at the levels of mRNA and protein by 51.3±2.1 and 11.6±2.2 fold respectively; this effect of gp120 on IL-6 expression was also demonstrated using primary human fetal astrocytes. A similar effect on IL-6 expression was observed when primary astrocytes were treated with gp120 protein derived from different strains of X4 and R5 tropic HIV-1. The induction of IL-6 could be abrogated by use of gp120-specific siRNA. Furthermore, this study showed that the NF-κB pathway is involved in gp120-mediated IL-6 over-expression, as IKK-2 and IKKβ inhibitors inhibited IL-6 expression by 56.5% and 60.8%, respectively. These results were also confirmed through the use of NF-κB specific siRNA. We also showed that gp120 could increase the phosphorylation of IκBα. Furthermore, gp120 transfection in the SVGA cells increased translocation of NF-κB from cytoplasm to nucleus. These results demonstrate that HIV-1 gp120-mediated over-expression of IL-6 in astrocytes is one mechanism responsible for neuroinflammation in HIV-infected individuals and this is mediated by the NF-κB pathway

Can occupational therapist-led home environmental assessment prevent falls in older people? A modified cohort randomised controlled trial protocol

INTRODUCTION: Falls and fall-related injuries are a serious cause of morbidity and cost to society. Environmental hazards are implicated as a major contributor to falls among older people. A recent Cochrane review found an environmental assessment, undertaken by an occupational therapist, to be an effective approach to reducing falls. However, none of the trials included a cost-effectiveness evaluation in the UK setting. This protocol describes a large multicentre trial investigating the clinical and cost-effectiveness of environmental assessment and modification within the home with the aim of preventing falls in older people. METHODS AND ANALYSIS: A two-arm, modified cohort randomised controlled trial, conducted within England, with 1299 community-dwelling participants aged 65 years and above, who are at an increased risk of falls. Participants will be randomised 2:1 to receive either usual care or home assessment and modification. The primary outcome is rate of falls (falls/person/time) over 12 months assessed by monthly patient self-report falls calendars. Secondary self-reported outcome measures include: the proportion of single and multiple fallers, time to first fall over a 12-month period, quality of life (EuroQoL EQ-5D-5L) and health service utilisation at 4, 8 and 12 months. A nested qualitative study will examine the feasibility of providing the intervention and explore barriers, facilitators, workload implications and readiness to employ these interventions into routine practice. An economic evaluation will assess value for money in terms of cost per fall averted. ETHICS AND DISSEMINATION: This study protocol (including the original application and subsequent amendments) received a favourable ethical opinion from National Health Service West of Scotland REC 3. The trial results will be published in peer-reviewed journals and at conference presentations. A summary of the findings will be sent to participants. TRIAL REGISTRATION NUMBER: ISRCTN22202133; Pre-results

Effectiveness of a nurse-led intensive home-visitation programme for first-time teenage mothers (Building Blocks):a pragmatic randomised controlled trial

SummaryBackgroundMany countries now offer support to teenage mothers to help them to achieve long-term socioeconomic stability and to give a successful start to their children. The Family Nurse Partnership (FNP) is a licensed intensive home-visiting intervention developed in the USA and introduced into practice in England that involves up to 64 structured home visits from early pregnancy until the child's second birthday by specially recruited and trained family nurses. We aimed to assess the effectiveness of giving the programme to teenage first-time mothers on infant and maternal outcomes up to 24 months after birth.MethodsWe did a pragmatic, non-blinded, randomised controlled, parallel-group trial in community midwifery settings at 18 partnerships between local authorities and primary and secondary care organisations in England. Eligible participants were nulliparous and aged 19 years or younger, and were recruited at less than 25 weeks' gestation. Field-based researchers randomly allocated mothers (1:1) via remote randomisation (telephone and web) to FNP plus usual care (publicly funded health and social care) or to usual care alone. Allocation was stratified by site and minimised by gestation (<16 weeks vs ≥16 weeks), smoking status (yes vs no), and preferred language of data collection (English vs non-English). Mothers and assessors (local researchers at baseline and 24 months' follow-up) were not masked to group allocation, but telephone interviewers were blinded. Primary endpoints were biomarker-calibrated self-reported tobacco use by the mother at late pregnancy, birthweight of the baby, the proportion of women with a second pregnancy within 24 months post-partum, and emergency attendances and hospital admissions for the child within 24 months post-partum. Analyses were by intention to treat. This trial is registered with ISRCTN, number ISRCTN23019866.FindingsBetween June 16, 2009, and July 28, 2010, we screened 3251 women. After enrolment, 823 women were randomly assigned to receive FNP and 822 to usual care. All follow-up data were retrieved by April 25, 2014. 304 (56%) of 547 women assigned to FNP and 306 (56%) of 545 assigned to usual care smoked at late pregnancy (adjusted odds ratio [AOR] 0·90, 97·5% CI 0·64–1·28). Mean birthweight of 742 babies with mothers assigned to FNP was 3217·4 g (SD 618·0), whereas birthweight of 768 babies assigned to usual care was 3197·5 g (SD 581·5; adjusted mean difference 20·75 g, 97·5% CI −47·73 to 89·23. 587 (81%) of 725 assessed children with mothers assigned to FNP and 577 (77%) of 753 assessed children assigned to usual care attended an emergency department or were admitted to hospital at least once before their second birthday (AOR 1·32, 97·5% CI 0·99–1·76). 426 (66%) of 643 assessed women assigned to FNP and 427 (66%) 646 assigned to usual care had a second pregnancy within 2 years (AOR 1·01, 0·77–1·33). At least one serious adverse event (mainly clinical events associated with pregnancy and infancy period) was reported for 310 (38%) of 808 participants (mother–child) in the usual care group and 357 (44%) of 810 in the FNP group, none of which were considered related to the intervention.InterpretationAdding FNP to the usually provided health and social care provided no additional short-term benefit to our primary outcomes. Programme continuation is not justified on the basis of available evidence, but could be reconsidered should supportive longer-term evidence emerge.FundingDepartment of Health Policy Research Programme

Pre-Operative Cognitive Functioning and Inflammatory and Neuroendocrine Responses to Cardiac Surgery.

BACKGROUND: Cognitive functioning is linked to cardiac mortality and morbidity, but the mechanisms underlying this relationship are unclear. PURPOSE: To examine the relationship between pre-operative cognitive functioning and post-operative inflammatory and neuroendocrine responses in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: One-hundred ninety-three outpatients were screened to assess their cognitive function using the Montreal Cognitive Assessment (MoCA) on average 30 days prior to CABG surgery and provided blood samples for the measurement of interleukin (IL)-6 and C-reactive protein (CRP) and saliva samples for the measurement of diurnal cortisol. Participants were followed-up 4-8 days following surgery for the repeat measurement of IL-6 and CRP and 60 days after surgery for the measurement of diurnal salivary cortisol. RESULTS: Patients with low cognitive function (MoCA < 26) prior to surgery reached higher IL-6 concentrations in the days after surgery (β = -0.212, p = 0.021) and had greater cortisol output across the day 2 months after surgery (β = -0.179, p = 0.044). CONCLUSIONS: Low cognitive functioning is associated with a more negative pattern of biological response to surgery, indicative of poorer physical recovery. These pathways may contribute to the links between cognitive function and cardiovascular pathology

Emergence of Pituitary Adenoma in a Child during Surveillance: Clinical Challenges and the Family Members' View in an AIP Mutation-Positive Family.

Introduction: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are responsible for 15-30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion in AIP, aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting. Patients: An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke's cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier. Discussion: Out of the 14 members harbouring germline AIP mutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended in AIP mutation-positive families.Pedro Marques is supported by Barts and The London Charity Clinical Training Research Fellowship. Márta Korbonits’s project on familial pituitary adenomas is supported by the Medical Research Council, UK

A cross-over, randomised feasibility study of digitally printed versus hand-painted artificial eyes in adults: PERSONAL-EYE-S - a study protocol

ackground/objectives: Around 11,500 artificial eyes are required yearly for new and existing patients. Artificial eyes have been manufactured and hand-painted at the National Artificial Eye Service (NAES) since 1948, in conjunction with approximately 30 local artificial eye services throughout the country. With the current scale of demand, services are under significant pressure. Manufacturing delays as well as necessary repainting to obtain adequate colour matching, may severely impact a patient’s rehabilitation pathway to a normal home, social and work life. However, advances in technology mean alternatives are now possible. The aim of this study is to establish the feasibility of conducting a large-scale study of the effectiveness and cost-effectiveness of digitally printed artificial eyes compared to hand-painted eyes. Methods: A cross-over, randomised feasibility study evaluating a digitally-printed artificial eye with a hand-painted eye, in patients aged ≥18 years with a current artificial eye. Participants will be identified in clinic, via ophthalmology clinic databases and two charity websites. Qualitative interviews will be conducted in the later phases of the study and focus on opinions on trial procedures, the different artificial eyes, delivery times, and patient satisfaction. Discussion: Findings will inform the feasibility, and design, of a larger fully powered randomised controlled trial. The long-term aim is to create a more life-like artificial eye in order to improve patients’ initial rehabilitation pathway, long term quality of life, and service experience. This will allow the transition of research findings into benefit to patients locally in the short term and National Health Service wide in the medium to long term