Professor Simon Skene


Head of Department of Clinical and Experimental Medicine, Professor of Medical Statistics
BSc, MSc, PhD

Biography

My publications

Publications

Skene S, Kenward M (2010) The analysis of very small samples of repeated measurements II: A modified Box correction, Statistics in Medicine 29 (27) pp. pp2838-2856 Wiley
There is a need for appropriate methods for the analysis of very small samples of continuous repeated measurements. A key feature of such analyses is the role played by the covariance matrix of the repeated observations. When subjects are few it can be difficult to assess the fit of parsimonious structures for this matrix, while the use of an unstructured form may lead to a serious lack of power. The Kenward?Roger adjustment is now widely adopted as a means of providing an appropriate inferences in small samples, but does not perform adequately in very small samples. Adjusted tests based on the empirical sandwich estimator can be constructed that have good nominal properties, but are seriously underpowered. Further, when such data are incomplete, or unbalanced, or non?saturated mean models are used, exact distributional results do not exist that justify analyses with any sample size. In this paper, a modification of Box's correction applied to a linear model?based F?statistic is developed for such small sample settings and is shown to have both the required nominal properties and acceptable power across a range of settings for repeated measurements.
Athauda D, Maclagan K, Skene S, Bajwa-Joseph M, Letchford D, Chowdhury K, Hibbert S, Budnik N, Zampedri L, Dickson J, Li Y, Aviles-Olmos, I, Warner T T, Limousin P, Lees A J, Greig N H, Tebbs S, Foltynie T (2017) Exenatide once weekly versus placebo in Parkinson?s disease: a randomised, double-blind, placebo-controlled trial., The Lancet 390 (10103) pp. pp1664-1675 Elsevier
Background
Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial.

Methods
In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25?75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed.

Findings
Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI ?2·6 to 0·7) in the exenatide group and worsened by 2·1 points (?0·6 to 4·8) in the placebo group, an adjusted mean difference of ?3·5 points (?6·7 to ?0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions.

Interpretation
Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.

Funding
Michael J Fox Foundation for Parkinson's Research.

Skene S, Bunce C, Freemantle N, Dore C (2016) Ophthalmic statistics note 9: parametric versus non-parametric methods for data analysis, BMJ Open Ophthalmology 100 (7) pp. pp877-878 BMJ Publishing Group Ltd
INTRODUCTION/SCENARIO
Distributions of measured data are often well modelled by known probability distributions, which provide a useful description of their underlying properties such as location (average), spread (variation) and shape.
Statisticians use probability distributions to interpret and attribute meaning, draw conclusions and answer research questions using the measurements or data that
researchers gather during their studies. Different types of data follow different probability distributions, and these distributions are characterised by certain features
called parameters. Even the most statistically averse of researchers is likely to have heard of the normal distribution, which is often used to approximate the distribution of continuous or measurement data such as intraocular pressure, central retinal thickness and
degree of proptosis. The normal distribution follows a ?bell-shaped curve? (although with a rim stretching to ±infinity) the shape of which is specified by the mean and SD, with different values of each, giving rise to
different bell-shaped curves (see figure 1).
Other distributions such as the binomial and Poisson probability distributions are less commonly reported in ophthalmic research and are characterised by different
parameters. The binomial distribution is used for dichotomous data and is characterised by the probability of success, that is, the number of ?successes? out of a total number of observed events, for example, the proportion of graft transplants that fail within 6 months of transplantation. The Poisson distribution is used for counts data and is characterised by the mean number of
events, for example, endophthalmitis rates.
The assumption that the observed data follow such probability distributions allows a statistician to apply appropriate statistical tests, which are known as parametric tests. The normal distribution is a powerful tool provided the data plausibly arise from that
distribution or can be made to reasonably
approximate this following a suitable transformation
such as by taking natural logarithms to reduce asymmetry. The normal distribution also serves as an approximating
distribution to the Poisson or binomial distribution
under certain circumstances or can be used for large samples to approximate the distribution of the sample mean via the central limit theorem. Tests based on the
normal distribution are therefore extremely useful and form the basis of many analyses, the usual tests being z tests or t tests, which rely on approximate normality or normality, respectively.1 If we can assume a normal distribution, then we expect 95% of values to lie within 1.96 SDs of the mean.
Parametric tests make assumptions about the distribution of the data and sometimes it may be impossible to assess these assumptions, perhaps because the sample size is
small or because that data do not follow any of the more common probability distributions. Alternatively, we may be interested in making inferences about medians rather than means or about ordinal or ranked data. In such circumstances, statisticians may adopt an alternative class of statistical tests, which are known as non-parametric or distribution-free methods. These methods work by ranking the data in numerical order and analysing
these ranks rather than the actual measurements
observed. Two of the most well-known non-parametric methods are the Mann?Whitney test (or U test) and the Wilcoxon matched-pairs signed-rank test, which are
suitable for data from two unpaired samples or two paired samples, respectively.2 3
The Wilcoxon matched-pairs signed-rank test calculates the differences between each matched pair in the two samples and replaces their absolute values with their
ordered ranks (1, 2, 3, etc), ignoring zeros. Under the null hypothesis of no difference between samples, the sum of the positive and negative ranks should be similar. The
test statistic is usually taken to be the smaller of the two sums, and exact p values ca
Goldberg A, Thomson C, Brooking D, Rees E, Cumbers M, Tetlow M, Skene S, Cro S (2015) Novel patient engagement and recruitment strategies for an RCY of two NHS treatments for ankle osteoarthritis, Trials 16(S2) (094) pp. pp1-1 BioMed Central Ltd
TARVA is an NIHR HTA funded portfolio randomised
controlled trial (RCT) comparing total ankle replacement
(TAR) and arthrodesis (fusion) surgery in NHS
patients aged 50-85 with end-stage ankle arthritis. 328
patients will be randomly allocated to TAR or arthrodesis
on an equal basis.
Clinician and patient treatment equipoise is critical to
recruit surgeons and patients successfully.
The TARVA Trial team has developed novel surgeon
and patient engagement techniques involving technology
and multi-media tools to achieve our aims. Examples
include an award-winning video, a white-labelled patient
information brochure, professional newsletters and blogs,
and a particular focus on the use of social networking
tools to engage both investigators and patients.
The impartial trial information video featuring consultant foot and ankle surgeons and patients who have
undergone TAR or fusion surgery can be accessed through the trial website (http://anklearthritis.co.uk).
The pilot phase began with the randomisation of the
first patient in March 2015. An overview of our techniques alongside recruitment data accumulated until
November will be presented at the ICTM conference.
Howard Jo, Slee April E., Skene Simon, Inusa Baba, Kawadler Jamie, Downes Michelle, Gavlak Johanna, Koelbel Melanie, Stotesbury Hanne, Chorozoglou Maria, Tebbs Susan, Chakravorty Subarna, Awogbade Moji, Rees David C., Gupta Atul, Murphy Patrick B., Hart Nicholas, Sahota Sati, Nwosu Carol, Gwam Maureen, Saunders Dawn, Muthurangu Vivek, Barber Nathaniel, Ako Emmanuel, Thein Swee Lay, Marshall Melanie, Reading Isabel C, Cheng Man Ying Edith, Kirkham Fenella J., Liossi Christina (2018) Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial, Trials 19 (55) BioMed Central
Background

In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life.

Methods/Design

Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of

Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8?11, 12?15, 16?22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or

For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist.

The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment.

Discussion

Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events.

Trial registration

ISRCTN46012373. Registered on 10 July 2015.

Protocol Version: 6.0 Date: 24th December 2015

Sponsor: University Hospital Southampton. Sponsor?s protocol code: RHMCHIOT53

Skene S, Kenward M (2010) The analysis of very small samples of repeated
measurements I: An adjusted sandwich
estimator,
Statistics in Medicine 29 pp. pp2825-2837 Wiley
The statistical analysis of repeated measures or longitudinal data always requires the accommodation of the covariance structure of the repeated measurements at some stage in the analysis. The general linear mixed model is often used for such analyses, and allows for the specification of both a mean model and a covariance structure. Often the covariance structure itself is not of direct interest, but only a means to producing valid inferences about the response. Existing methods of analysis are often inadequate where the sample size is small. More precisely, statistical measures of goodness of fit are not necessarily the right measure of the appropriateness of a covariance structure and inferences based on conventional Wald-type procedures do not approximate sufficiently well their nominal properties when data are unbalanced or incomplete. This is shown to be the case when adopting the Kenward?Roger adjustment where the sample size is very small. A generalization of an approach to Wald tests using a bias-adjusted empirical sandwich estimator for the covariance matrix of the fixed effects parameters from generalized estimating equations is developed for Gaussian repeated measurements. This is shown to attain the correct test size but has very low power.
Goldberg A J, Zaidi R, Thomson C, Doré C J, Skene S S, Cro S, Round J, Molloy A, Davies M, Karski M, Kim L, Cooke P (2016) Total ankle replacement versus arthrodesis (TARVA): protocol for a multicentre randomised controlled trial, BMJ Open 6 (9) e012716 pp. pp1-7 BMJ Publishing Group Ltd
Introduction Total ankle replacement (TAR) or ankle arthrodesis (fusion) is the main surgical treatments for end-stage ankle osteoarthritis (OA). The popularity of ankle replacement is increasing while ankle fusion rates remain static. Both treatments have efficacy but to date all studies comparing the 2 have been observational without randomisation, and there are no published guidelines as to the most appropriate management. The TAR versus arthrodesis (TARVA) trial aims to compare the clinical and cost-effectiveness of TAR against ankle arthrodesis in the treatment of end-stage ankle OA in patients aged 50?85?years.

Methods and analysis TARVA is a multicentre randomised controlled trial that will randomise 328 patients aged 50?85?years with end-stage ankle arthritis. The 2 arms of the study will be TAR or ankle arthrodesis with 164 patients in each group. Up to 16 UK centres will participate. Patients will have clinical assessments and complete questionnaires before their operation and at 6, 12, 26 and 52?weeks after surgery. The primary clinical outcome of the study is a validated patient-reported outcome measure, the Manchester Oxford foot questionnaire, captured preoperatively and 12?months after surgery. Secondary outcomes include quality-of-life scores, complications, revision, reoperation and a health economic analysis.

Ethics and dissemination The protocol has been approved by the National Research Ethics Service Committee (London, Bloomsbury 14/LO/0807). This manuscript is based on V.5.0 of the protocol. The trial findings will be disseminated through peer-reviewed publications and conference presentations.

Trial registration number NCT02128555.

China L, Muirhead N, Skene SS, Shabir Z, De Maeyer R P H, Maini A A N, Gilroy D W, O'Brien AJ (2016) Albumin To prevenT Infection in chronic liveR failurE: study protocol for a single-arm feasibility trial, BMJ Open 6 (1) pp. pp1-6 BMJ Publishing Group
Abstract

Introduction Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds and inactivates this hormone. Human albumin solution could thus be repurposed as an immune restorative drug in these patients.

This feasibility study aims to determine whether it is possible and safe to restore serum albumin to >30?g/L and maintain it at this level in patients admitted with acute decompensated cirrhosis using repeated 20% human albumin infusions according to daily serum albumin levels.

Methods and analysis Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) stage 1 is a multicentre, open label dose feasibility trial. Patients with acutely decompensated cirrhosis admitted to hospital with a serum albumin of

Ethics and dissemination Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001).

Results Will be disseminated through peer reviewed journals and international conferences. Recruitment of the first participant occurred on 26/05/2015.

Trial registration number The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the NIHR (ISRCTN 14174793). This manuscript refers to V.4.0 of the protocol; Pre-results.

China L, MainiMaini A, Skene S, Shabir Z, Sylvestre Y, Colas R A, Ly L, Salles N B, Belloti V, Dalli J, Gilroy D W, O?Brien* A (2018) Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease, Clinical Gastroenterology and Hepatology 16 (5) pp. pp738-747 Elsevier
Background & Aims
Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids.

Methods
We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients? samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration.

Results
At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P

Conclusions
Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793).

O'Brien A, China L, Forrest E, Ryder S, Wright G, Portal J, O'Beirne J, Shabir Z, Skene S, Chandler T, Garcia-Hernandez J, Blackstone J (2016) Is human albumin solution really the best resuscitation fluid for patients with advanced cirrhosis?, Gut 65 (8) BMJ Publishing Group Ltd
We read with interest the revised consensus recommendations for management of acute kidney injury (AKI) ) in cirrhosis by the International Club of Ascites.1 We are concerned that plasma volume expansion only with albumin is recommended for stage 2 and 3 AKI and do not believe that this represents a balanced view of the available evidence. No one doubts that fluid resuscitation is an integral part of the management of AKI; however, studies to date have not established class 1 evidence for an advantage of the use of albumin over other colloids or crystalloids.
China L, Skene S, Shabir Z, Maini A, Syvestre Y, Bennett K, Bevan S, O'Beirne J, Forrest E, Portal J, Ryder S, Wright G, Gilroy D W, O'Brien A (2018) Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial, Clinical Gastroenterology and Hepatology 16 (5) pp. pp748-755 W B Saunders
Background & Aims

Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2?mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.

Methods

We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels.

Results

The patients? mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin e30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded.

Conclusions

In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.

Unfortunately, the original version of this article [1] contained an error. The title was written as ?Novel patient engagement and recruitment strategies for an RCY of two NHS treatments for ankle osteoarthritis - total ankle replacement versus arthrodesis - the TARVA trial? and should instead have been written as follows: ?Novel patient engagement and recruitment strategies for an RCT of two NHS treatments for ankle osteoarthritis - total ankle replacement versus arthrodesis - the TARVA trial? where RCY should be RCT which stands for Randomised Controlled Trial.
China L, Fullerton J, George M, Skene S, Shabir Z, Gilroy D, O'Brien A (2015) Attire: albumin to prevent infection in chronic liver failure, JOURNAL OF HEPATOLOGY 62(S2) pp. ppS853-S853 ELSEVIER SCIENCE BV
Background and Aims: Patients with cirrhosis are at a greatly increased risk of severe bacterial infection with survival directly related to extra-hepatic organ dysfunction. A defective innate immune response is considered to underlie this risk. There is however no medical strategy to restore immune competence in
these patients.
Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in acutely decompensated (AD) cirrhosis. PGE2 is more bioavailable because of decreased serum albumin levels in AD patients as albumin binds PGE2. The binding capacity of endogenous albumin is also known to be defective in cirrhosis. Human Albumin Solution (HAS), a safe and common intervention, could thus be repurposed as an immune restorative drug in AD
patients.
The primary aim of ATTIRE is to determine if raising serum albumin to >30 g/L in patients with decompensated cirrhosis will decrease rates of infection, extra hepatic organ dysfunction and death.
Rodriguez-Mateos Ana, Weber Timon, Skene Simon, Ottaviani Javier I, Crozier Alan, Kelm Malte, Schroeter Hagan, Heiss Christian (2018) Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: Randomized-controlled, double-masked intervention trial, The American Journal of Clinical Nutrition 108 (6) nqy229 pp. 1229-1237 American Society for Nutrition
Background:

Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are comprised principally of the monomer, (?)-epicatechin (~20%) with a degree of polymerisation of 1 (DP1), and oligomeric procyanidins (~80%, DP2-10).

Objective:

To investigate the relative contribution of procyanidins and (?)-epicatechin to CF intake-related improvements in vascular function in healthy volunteers.

Design:

In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men, (18-35 years), consumed once daily for 1 month (a) a DP1-10 cocoa extract containing 130 mg of (?)-epicatechin and 560 mg of procyanidins (b) a DP2-10 cocoa extract containing 20 mg (?)-epicatechin and 540 mg procyanidins or (c) a Control that was flavanol-free with identical micro- and macronutrient composition. (ClinicalTrials.gov NCT02728466)

Results:

Consumption of DP1-10, but neither DP2-10 nor the Control, significantly increased flow-mediated vasodilation (primary endpoint), and the level of structurally-related (?)-epicatechin metabolites (SREMs) in the circulatory system, while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1-10 and DP2-10 as compared to the Control.

Conclusions:

CF-related improvements in vascular function predominantly relate to intake of flavanol monomers and circulating SREMs in healthy humans, but not to the more abundant procyanidins and gut microbiome-derived CF-catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily that of (-)-epicatechin.

Stern Manuel, Broja Melanie, Sansone Roberto, Gröne Michael, Skene Simon, Liebmann Joerg, Suschek Christoph, Born Matthias, Kelm Malte, Heiss Christian (2018) Blue light exposure decreases systolic blood pressure, arterial stiffness, and improves endothelial function in humans, European Journal of Preventive Cardiology 25 (17) pp. 1875-1883 SAGE Publications
Aims:

Previous studies have shown that ultraviolet light can lead to release of nitric oxide (NO) from the skin and decrease blood pressure. In contrast to visible light local application of UV light bears a cancerogenic risk. Here, we investigated whether whole body exposure to visible blue light can also decrease blood pressure and increase endothelial function in healthy subjects.

Methods:

In a randomized cross-over study, 14 healthy male subjects were exposed on 2 days to monochromatic blue light or blue light with a filter foil (control light) over 30 min. We measured blood pressure (primary endpoint), heart rate, forearm vascular resistance, forearm-blood-flow, endothelial function (flow-mediated dilation), pulse wave velocity, and plasma NO species (NOx), nitrite, and nitroso compounds (RXNO) (secondary endpoints) during and up to 2 hours after exposure.

Results:

Blue light exposure significantly decreased systolic blood pressure and increased heart rate as compared to control. In parallel, blue light significantly increased forearm-blood-flow, flow-mediated dilation, circulating NOx and RXNO while it decreased forearm vascular resistance and pulse wave velocity.

Conclusion:

Whole body irradiation with visible blue light at real world doses improves blood pressure, endothelial function, and arterial stiffness by NO released from photolabile intracutanous NO metabolites into circulating blood.

Athauda Dilan, Maclagan Kate, Budnik Natalia, Zampedri Luca, Hibbert Steve, Aviles-Olmos Iciar, Chowdhury Kashfia, Skene Simon S., Limousin Patricia, Foltynie Thomas (2018) Post hoc analysis of the Exenatide-PD trial-Factors that predict response, European Journal of Neuroscience 49 (3) pp. 410-421 Wiley-Blackwell
Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson?s disease in a randomized, placebo-controlled trial. In addition, there were trends favouring the exenatide group in assessments of nonmotor symptoms, cognition, and quality of life. The aim of this exploratory post hoc analysis was to generate new hypotheses regarding (a) whether candidate baseline factors might predict the magnitude of response to exenatide; and (b) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multi-variate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, nonmotor symptoms, cognition, and quality of life after 48-weeks treatment with exenatide were evaluated among post hoc subgroups defined by age, motor phenotype, disease duration, disease severity, body mass index (BMI), and insulin resistance. In the subgroup analyses, exenatide once- weekly was associated with broadly improved outcome measures assessing motor severity, nonmotor symptoms, cognition, and quality of life across all subgroups, however, tremor- dominant phenotype and lower Movement Disorder Society-Sponsored Revision of the Unified Parkinson?s Disease Rating Scale (MDS-UPDRS) Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of gluacagon-like peptide-1 (GLP-1) receptor agonists in Parkinson?s disease (PD).
Slee April E, Kawadler Jamie M, Koelbel Melanie, Stotesbury Hanne, Rees David C, Pelidis Maria, Howard Jo, Thein Swee Lay, Skene Simon, Sati Sahota, Nwosu Carol, Gwam Maureen, Saunders Dawn, Gavlak Johanna C, Atul Gupta, Sarkaria Simrat, Liossi Christina, Kirkham Fenella J, Inusa Baba (2017) Prevention of Morbidity in Sickle Cell Disease Phase II (Improvement of Cognition in children with Sickle Cell Disease with Auto-adjusting Continuous Positive Airways Pressure: Phase II) (POMS 2b paediatric cohort), BLOOD 130 (Sup 1) 3556 AMER SOC HEMATOLOGY
Background:
Complications in sickle cell anemia (SCA, HbSS) include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation. These effects can be compounded by obstructive sleep apnea (OSA).However, there is concern that oxygen supplementation in SCA may lead to bone marrow suppression. Continuous Positive Airways Pressure (CPAP) is an accepted treatment for OSA in the general population and prevents dips in oxygen saturation.. The aim of this single-blind, randomised, controlled phase II trial is to compare Auto-adjusting CPAP (APAP) with standard care to standard care alone in subjects with HbSS to determine whether the intervention is safe and improves Cancellation, a measure of selective attention and processing speed.

Methods:
Eligibility criteria included ability to provide informed consent, age >8 and

Minimisation/stratification factors were age group (8-11, 12-15 years), silent infarction on MRI, minimum overnight oxygen saturation >90% or

APAP adherence was defined as using APAP for an average of 4 hours a night for >50% of the time and was recorded using software documenting hours of use each night. Participant support in terms of appropriate facemask and facilitating adherence were provided by an unblinded sleep physiologist.

Full blood counts were obtained at baseline, 2 weeks, 3 months and 6 months.

Data were analysed by intention-to-treat. The primary outcome is change in the Cancellation subtest from the Wechsler scales, and secondary outcomes include general cognitive functioning, assessed at baseline and after 6 months of treatment by assessors blind to treatment assignment. Analysis of Covariance (ANCOVA) models, adjusted for minimisation factors, were used to calculate least-square mean changes from baseline to 6 months.

Results:
30 children (18 boys; median age 12.5; range 7.9-16 years) with SCA were randomised to standard care + APAP (n=15) or standard care alone (n=15) for 6 months. One child in the standard care alone arm withdrew after 6 weeks, and 8 children in the APAP arm were not adherent to treatment. Increase in cancellation score was numerically greater in the APAP arm (mean 1.46, SE 0.59 vs 1.01, SE 0.61) but this was not significant (mean difference 0.44, 95% CI: -1.42; 2.31; p=0.626). Increase in Cancellation score was greater (mean 2.63; 95%CI: 0.95, 4.30) in those whose adherence was in the highest quartile (> 2.4 hours/night) compared with the other 3 quartiles (mean 0.71, 95%CI: -0.32, 1.75; mean difference 1.91, 95%CI: -0.06, 3.88; p=0.057). In subjects assigned to APAP, cancellation scores were significantly higher with hydroxyurea use (p=0.01). There was no evidence of decline in haemoglobin in either group; hydroxyurea use was associated with an increase in haemoglobin (p=0.01). There were 7 subjects with serious adverse events in the standard care alone arm, compared to 3 in the APAP + standard care arm, all related to hospital admission for pain.

Discussion:
APAP for 6 months is feasible and safe in children with SCA. Alhough >50% were not adherent by the pre-defined definition, those who were compliant appeared to have more benefit in terms of improvement in attention/processing speed. There appears to be an interaction with HU use, consistent with the importance of oxygen supply and carriage for brain function. If delivery of the intervention can be improved, avoidance of oxygen desaturation with overnight respiratory support alongside HU use may play a role in improving cognition in SCD.

Disclosures: No relevant conflicts of interest to declare.

Athauda Dilan, Gulyani Seema, Karnati Hanuma kumar, Li Yazhou, Tweedie David, Mustapic Maja, Chawla Sahil, Chowdhury Kashfia, Skene Simon S., Greig Nigel H., Kapogiannis Dimitrios, Foltynie Thomas (2019) Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease, JAMA Neurology 76 (4) American Medical Association
Importance: Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge.

Objective: To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways.

Design, Setting, and Participants: Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti?L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017.

Main Outcomes and Measures: The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways.

Results: Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P

Conclusions and Relevance: The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.

Dyer J, Skene S, Crovetto F, Figueras F, Gratacos E, David A, Spencer R (2018) Assessing women's experiences of taking part in research during pregnancy., BJOG: An International Journal of Obstetrics & Gynaecology 125 (S2) pp. 15-29 Wiley
Becares Natalia, Härmälä Suvi, China Louise, Colas Romain A., Maini Alexander A., Bennet Kate, Skene Simon S., Shabir Zainib, Dalli Jesmond, O?Brien Alastair (2019) Immune Regulatory Mediators in Plasma from Patients with Acute Decompensation are Associated With 3-month Mortality, Clinical Gastroenterology and Hepatology Elsevier

Background & Aims

Infection is a common cause of death in patients with cirrhosis. We investigated the association between the innate immune response and death within 3 months of hospitalization.

Methods

Plasma samples were collected on days 1, 5, 10, and 15 from participants recruited into the albumin to prevent infection in chronic liver failure feasibility study. Patients with acute decompensated cirrhosis were given albumin infusions at 10 hospitals in the United Kingdom. Data were obtained from 45 survivors and 27 non-survivors. We incubated monocyte-derived macrophages from healthy individuals with patients? plasma samples and measured activation following lipopolysaccharide administration, determined by secretion of tumor necrosis factor and soluble mediators of inflammation. Each analysis included samples from 4 to 14 patients.

Results

Plasma samples from survivors vs non-survivors had different inflammatory profiles. Levels of prostaglandin E2 were high at times of patient hospitalization and decreased with albumin infusions. Increased levels of interleukin 4 (IL4) in plasma collected at day 5 of treatment were associated with survival at 3 months. Incubation of monocyte-derived macrophages with day 5 plasma from survivors, pre-incubated with a neutralizing antibody against IL4, caused a significant increase in tumor necrosis factor production to the level of non-survivor plasma. Although baseline characteristics were similar, non-survivors had higher white cell counts and levels of C-reactive protein and renal dysfunction.

Conclusions

We identified profiles of inflammatory markers in plasma that are associated with 3-month mortality in patients with acute decompensated cirrhosis given albumin. Increases in prostaglandin E2 might promote inflammation within the first few days after hospitalization, and increased levels of plasma IL4 at day 5 are associated with increased survival. Clinicaltrialsregister.eu: EudraCT 2014-002300-24

China Louise, Skene Simon S, Bennett Kate, Shabir Zainib, Hamilton Roseanna, Hamilton Scott, Chandler Torsten, Maini Alexander A, Becares Natalia, Gilroy Derek, Forrest Ewan H, O'Brien Alastair (2018) ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial, BMJ Open 8 (10) e023754 BMJ Publishing Group
Introduction: Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds to and inactivates this immune-suppressive lipid mediator. Human albumin solution (HAS) could thus be
repurposed as an immune-restorative drug in these patients. This is a phase III randomised controlled trial (RCT) to verify whether targeting a serum albumin level of e35 g/L in hospitalised patients with decompensated cirrhosis using repeated intravenous infusions of 20% HAS
will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or discharge if

Methods and analysis: Albumin To prevenT Infection in chronic liveR failurE stage 2 is a multicentre, openlabel, interventional RCT. Patients with decompensated cirrhosis admitted to the hospital with a serum albumin of the UK.

Ethics and dissemination: Research ethics approval was given by the London-Brent research ethics committee (ref:15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001?0001). The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the National Institute for Health Research (ISRCTN 14174793). This manuscript refers to version 6.0 of the protocol. Results will be disseminated through peer-reviewed journals and international conferences. Recruitment of the first participant occurred on 25 January 2016.

Athauda D., Budnik N., Chowdhury K., Skene S., Foltynie T. (2018) The effect of exenatide on specific non-motor symptoms in Parkinson?s disease ? a post-hoc analysis., European Journal of Neurology 25 pp. 277-573 Wiley
Becares N., Harmala S., China L., Skene S.S., Bennett K., Shabir Z., O?brien A. (2018) Lessons from ATTIRE feasibility study: differential inflammatory response profiles following treatment with albumin correlate with 6 months survival, Journal of Hepatology 68 (S1) pp. S10-S11 Elsevier
Athauda Dilan, Maclagan Kate, Budnik Natalia, Zampedri Luca, Hibbert Steve, Skene Simon S., Chowdhury Kashfia, Aviles-Olmos Iciar, Limousin Patricia, Foltynie Thomas (2018) What Effects Might Exenatide have on Non-Motor Symptoms in Parkinson?s Disease: A Post Hoc Analysis, Journal of Parkinson's Disease 8 (2) pp. 247-258 IOS Press

BackgroundExenatide is a GLP-1 receptor agonist that was recently studied for potential disease-modifying effects in a
randomised, placebo-controlled clinical trial in patients with moderate stage Parkinson?s disease, and showed positive effects
on the motor severity of the disease which were sustained 12 weeks beyond the period of exenatide exposure. Analysis of
pre-defined secondary outcomes revealed no statistically significant differences between patients treated with exenatide in
total non-motor symptom burden and overall quality of life measures.

Objective:The response of individual non-motor symptoms to an intervention may vary and thus this post hoc analysis was
conducted to explore the possible effects of exenatide compared to placebo on individual non-motor symptoms.

Results:Compared to placebo, patients treated with exenatide-once weekly had greater improvements in individual domains
assessing mood/depression across all observer-rated outcome measures after 48 weeks including the ?mood/apathy? domain
of the NMSS, ?3.3 points (95% CI ?6.2, ?0.4), p = 0.026; the ?mood? score (Q1.3+Q1.4 of the MDS-UPDRS Part 1), ?0.3
points (95%CI ?0.6, ?0.1), p = 0.034; and a trend in the MADRS total score, ?1.7 points (95%CI ?3.6, 0.2), p = 0.071. In
addition, there was an improvement in the ?emotional well-being? domain of the PDQ-39 of 5.7 points ((95%CI ?11.3, ?0.1),
p = 0.047 though these improvements were not sustained 12 weeks after exenatide withdrawal. At 48 weeks these changes
were of a magnitude that would be subjectively meaningful to patients and were not associated with changes in motor severity
or other factors, suggesting exenatide may exert independent effects on mood dysfunction.

Conclusions: These exploratory findings will contribute to the design of future trials to confirm the extent of motor and
non-motor symptom effects of exenatide in larger cohorts of patients.