Simon Skene is Professor of Medical Statistics at the University of Surrey and Director of Surrey Clinical Trials Unit and Clinical Research Facility.
Simon has over 20 years’ experience as a medical statistician in teaching and research, including the design and analysis of studies investigating medicinal products, advanced therapies, diagnostic accuracy and surgery. His PhD focused on the analysis of very small samples of repeated measurements, addressing small sample issues in longitudinal analysis. He is a Fellow of the Royal Statistical Society and has consultancy experience in the pharmaceutical industry.
As Head of Statistics at the UCL Comprehensive Clinical Trials Unit, he provided leadership and statistical oversight on UK trials coordinated by the unit across phases I-III in multiple therapeutic areas including hepatology and gastroenterology, ophthalmology, neurology and surgery.
Simon's appointment at University of Surrey combines the role of Director of the Clinical Trials Unit (CTU) and Clinical Research Facility (CRF) with leadership in statistics to support decision based practice in medicine. He is additionally Head of Department of Clinical and Experimental Medicine which brings together the CTU, CRF and Surrey Sleep Research Centre (SSRC) with complementary sections comprising Research Design Service - South East (RDS-SE; Surrey), Surrey Health Economics Centre (SHEC), Clinical Medicine and Statistical Multi-Omics. The department is dedicated to academic excellence in education and the delivery of clinical research in health and disease.
18 MAY 2021
Vinehealth and University of Surrey awarded £1m grant to trial a support app for patients undergoing cancer treatment
Associate Editor (Statistics) for the journal Osteoarthritis and Cartilage
Regional Advisory Panel member for NIHR Research for Patient Benefit (RfPB) South East and Central
Study question: Does remote monitoring of the side-effects of cancer chemotherapy with more timely intervention reduce symptom burden, anxiety, supportive care needs, work limitations and increase quality of life, and self-efficacy. Methods: A multicentre randomised controlled trial in Austria, Greece, Norway, Republic of Ireland and UK was conducted over 36 months in 829 patients with non-metastatic breast cancer, colorectal cancer, Hodgkin’s Disease, or non-Hodgkin’s lymphoma receiving first-line adjuvant chemotherapy or chemotherapy for the first time in five years. Patients were randomised to remote monitoring system ASyMS (intervention group) or standard care (control group) over 6 cycles of chemotherapy. The primary outcome was symptom burden measured on the Memorial Symptom Assessment Scale (MSAS). Study answer and limitations: For the intervention group, symptom burden remained at pre-chemotherapy treatment levels, while controls reported an increase from cycle 1 onwards and hence showing a significant benefit.Analysis of MSAS sub-domains also indicated significant benefit in favour of ASyMS with reductions in global distress; psychological factors and physical symptoms. Limitations included not covering all cancers, with the highest proportion of patients having breast cancer and blinding was not possible due to the nature of the intervention. What this study adds: Our study showed significant benefit in reduction of symptom burden, anxiety, supportive care needs and increase in quality of life and self-efficacy. Remote monitoring systems will be vital for future services, particularly with blended models of care delivery arising from the COVID-19 pandemic.
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.
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.
Unfortunately, the original version of this article  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.
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 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.
Objective: To further explore the mechanism of action of exenatide, a glucagon-like peptide-1 agonist, underlying the positive effects on motor function in a recently reported in a clinical trial of Parkinson’s disease. Background: Exenatide, a glucagon-like peptide-1 agonist licensed for the treatment of Type 2 diabetes was recently found to have beneficial effects on motor function in a placebo-controlled trial in patients with moderate stage Parkinson’s disease (PD). Accumulating evidence suggests that impaired insulin and Akt signalling with consequent relative deactivation of cell survival pathways play a role in PD pathogenesis. Design/Methods: We isolated serum extracellular vesicles (EVs) enriched for neuronal origin from trial participants and measuring concentrations of total and phosphorylated signalling proteins at various timepoints. Neuronal insulin receptor mediated downstream signalling cascades were investigated by measuring levels of IRS-1 proteins, whereas evidence of potential Akt and MAPK pathway activation was determined by measurement of total and phosphorylated forms of key kinases Akt, mTOR, GSK-3B, p38, Erk1/2 and JNK. Results: We found that, compared to placebo, peripherally administered exenatide can engage neuronal signalling pathways and promote activating phosphorylations on IRS-1 tyrosine residues and downstream substrates including Akt and mechanistic target of rapamycin (mTOR). Furthermore, the beneficial clinical effects of exenatide on motor function were associated with EV biomarker changes suggesting a reduction in neuronal insulin resistance and concomitant activation of mTOR signalling Conclusions: The results suggest target engagement of insulin/Akt/mTOR signalling pathways in neurons by exenatide and provide a mechanistic context for the recent clinical findings of the trial.
Background The total ankle replacement versus ankle arthrodesis (TARVA) trial aims to determine which surgical procedure confers the greatest improvement in pain-free function for patients with end-stage ankle osteoarthritis. Both procedures are effective but there has not yet been a direct comparison to establish which is superior. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. Design and methods TARVA is a randomised, un-blinded, parallel group trial of total ankle replacement versus ankle arthrodesis. The primary outcome is the Manchester-Oxford Foot Questionnaire walking/standing domain score at 52 weeks post-surgery. Secondary outcomes include measures of pain, social interaction, physical function, quality of life, and range of motion. We describe in detail the statistical aspects of TARVA: the outcome measures, the sample size calculation, general analysis principles including treatment of missing data, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses. Discussion The TARVA statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in January 2020 when follow-up for the trial is completed.
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
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 ≥35 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
Background Chronic viral hepatitis (CVH) is a leading contributor to the UK liver disease epidemic, with global migration from high prevalence areas (e.g., South Asia). Despite international guidance for testing high-risk groups in line with elimination targets, there is no consensus on how to achieve this. The objectives of this study were to assess the following: (1) the feasibility of recruiting South Asian migrants to view an educational film on CVH, (2) the effectiveness of the film in promoting testing and increasing knowledge of CVH, and (3) the methodological issues relevant to scale-up to a randomized controlled trial. Methods South Asian migrants were recruited to view the film (intervention) in community venues (primary care, religious, community), with dried blood spot CVH testing offered immediately afterwards. Pre/post-film questionnaires assessed the effectiveness of the intervention. Results Two hundred and nineteen first-generation migrants ≥18 years of age (53% female) were recruited to view the film at the following sites: religious, n = 112 (51%), community n = 98 (45%), and primary care, n = 9 (4%). One hundred and eighty-four (84%) underwent CVH testing; hepatitis B core antibody or hepatitis C antibody positivity demonstrated exposure in 8.5%. Pre-intervention (n = 173, 79%) and post-intervention (n = 154, 70%) questionnaires were completed. Conclusions This study demonstrated the feasibility of recruiting first-generation migrants to view a community-based educational film promoting CVH testing in this higher risk group, confirming the value of developing interventions to facilitate the global World Health Organization plan for targeted case finding and elimination, and a future randomized controlled trial. We highlight the importance of culturally relevant interventions including faith and culturally sensitive settings, which appear to minimize logistical issues and effectively engage minority groups, allowing ease of access to individuals ‘at risk’.
Introduction/Background MIRRORS is a UK based prospective feasibility study opened June 2020, following ethics approval. Its purpose is to establish the feasibility of launching a randomised control trial (RCT) of Robotic interval debulking surgery for ovarian cancer (including cancer of the fallopian tube & peritoneum) MIRRORS-RCT in the future. MIRRORS will focus on the feasibility of obtaining consent from women and the acceptability of Robotic interval debulking surgery for advanced ovarian cancer. Methodology Women will be identified through the Gynaecological Oncology multi-disciplinary team meeting. Inclusion Criteria adult women ≥18 years with stage IIIc–IVb ovarian cancer (including cancer of the fallopian tube & peritoneum) undergoing neo–adjuvant chemotherapy considered suitable for interval debulking surgery (IDS). ≤8 cm pelvic mass on CT Exclusion Criteria Pelvic Mass >8 cm open surgical approach considered necessary following MDT review. Women lacking capacity to the extent they are unable to understand or complete trial documentation/questionnaires will be excluded from the trial. Exclusion CriteriaMIRRORS inclusion criteria are intentionally wide, not restricting by Body Mass Index (BMI), patient comorbidity or Ca125 values. Surgery will commence with an initial laparoscopic assessment followed by a decision to proceed to robotic or open interval debulking surgery. The aim of surgery is to remove all visible disease safely by whichever route. If conversion to open surgery is required to complete this, then it will be done. Results All women recruited to MIRRORS, whether eventually undergoing robotic or open surgery, will be followed up to assess recovery, complication rate, pain and quality of life. If the following Success Criteria are met, we will progress to MIRRORS-RCT: ≥20% of women eligible for the study accept inclusion in MIRRORS. Robotic IDS Complication rate is not higher than for open interval debulking surgery Conversion to open surgery rate not greater than 50% in patient group deemed suitable for Robotic IDS following initial diagnostic laparoscopy.
Introduction/Background: Inoperable bowel obstruction (IBO) occurs in up to 50% of patients diagnosed with ovarian cancer. Nutrition support for patients with IBO is challenging. Parenteral feeding (PN) is the recommended route for patients with a prognosis of > 2 months, however there is little evidence that it improves quality of life and the cost of it is very high. If PN is not available patients are frequently discharged home from hospital with sips of clear fluids only. Management of inoperable bowel obstruction remains a major challenge and clear guidelines are needed. Elemental diet (ED) is a liquid diet that contains proteins in the form of amino acids, fats in the form of medium chain triglycerides, vitamins and trace minerals. ED is almost completely absorbed in the upper small intestine. Methodology The primary objective of the study was to establish if ED can be used as an alternative to home PN in patients with IBO. The secondary aim was to examine the impact of ED on quality of life. The primary endpoints of the study were acceptability and tolerability of ED with respect to taste, and incidence of vomiting and pain. The secondary endpoints included the number of patients alive at the end of the study, quality of life, nutritional intake, and the number of women who can tolerate ED and subsequently be treated with palliative chemotherapy (as per standard of care).Results29 women with IBO caused by metastatic ovarian cancer were recruited into the EDMONd study. Of those 8 could not complete the trial due to disease progression, and 2 had missing data that was deemed irretrievable, leaving 19 patients who contributed data to the primary endpoint analysis. The mean age of the patients who continued the trial was 68 (SD 12.5). Preliminary analysis shows that 68.4% of patients met the primary endpoint and tolerated ED; the ED did not worsen the vomiting or pain as measured by Memorial Symptoms Assessment Scale. At baseline 72% of patients experienced vomiting and this number reduced to 28% by the end of week1 of the study and to 23.5% by the end of week 2. 96% of patients reported pain at baseline and this proportion reduced to 72% and 76% by the end of week 1 and 2 respectively. Conclusion ED is well tolerated by patients with IBO and can provide an acceptable feeding option for this group of patients.
Introduction/Background: Ovarian cancer is the most lethal gynaecological malignancy and the 6th most common cancer among women globally. The incidence of malignant bowel obstruction (MBO) in patients with advanced disease is up to 51%. It presents a very distressing scenario for patients, their families and clinicians. Management of MBO can be divided into surgical and medical management. Surgical management can involve direct resection, bypass surgery or stoma formation. Medical management includes endoscopic procedures, nasogastric tubes for decompression, bowel rest, parenteral feeding and symptom control such as chemotherapy, steroids, antisecretory drugs, analgesia and anti-emetics. The rationale in choosing between surgical or medical management strategies is not well defined. High perioperative morbidity (up to 90%) and mortality (up to 40%) can make surgery a risky choice and there is increasing evidence that non-surgical management can significantly improve symptoms and quality of life. The objective of this study was to evaluate the outcomes of patients with advanced ovarian cancer who undergo non-surgical management of malignant bowel obstruction and conduct a meta-analysis to estimate median survival. Methodology: A literature search was carried out using the Pubmed, Embase and Medline online libraries up until November 2019. We also searched abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Relevant studies that met the inclusion criteria were independently selected by two of the co-authors and the data extracted and analysed separately. Results: In total 24 studies were found to be relevant for the systematic review and 9 met the eligibility criteria for the meta-analysis, a total of 2236 patients were included. Median survival for patients managed medically for bowel obstruction was 44 days (95% CI 38–49 days, I2 = 0%, P = 0.128).Abstract 296 Figure 1ConclusionThe quality of the included studies was relatively low, however the evidence shows that non-surgical management of bowel obstruction in advanced ovarian cancer patients results in a short survival period, but with controlled symptoms. Where quality of life is the main concern, this may be a feasible and effective strategy.
Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown. We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment. A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group. In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).
Oral morphine is frequently used for breakthrough pain but the oral route is not always available and absorption is slow. Transmucosal diamorphine is administered by buccal, sublingual or intranasal routes, and rapidly absorbed. To explore the perspectives of healthcare professionals in the UK caring for children with life-limiting conditions concerning the assessment and management of breakthrough pain; prescribing and administration of transmucosal diamorphine compared with oral morphine; and the feasibility of a comparative clinical trial. Three focus groups, analysed using a Framework approach. Doctors, nurses and pharmacists ( = 28), caring for children with life-limiting illnesses receiving palliative care, participated. Oral morphine is frequently used for breakthrough pain across all settings; with transmucosal diamorphine largely limited to use in hospices or given by community nurses, predominantly buccally. Perceived advantages of oral morphine included confidence in its use with no requirement for specific training; disadvantages included tolerability issues, slow onset, unpredictable response and unsuitability for patients with gastrointestinal failure. Perceived advantages of transmucosal diamorphine were quick onset and easy administration; barriers included lack of licensed preparations and prescribing guidance with fears over accountability of prescribers, and potential issues with availability, preparation and palatability. Factors potentially affecting recruitment to a trial were patient suitability and onerousness for families, trial design and logistics, staff time and clinician engagement. There were perceived advantages to transmucosal diamorphine, but there is a need for access to a safe preparation. A clinical trial would be feasible provided barriers were overcome.
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 < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. 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).
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.
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.
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 can be found using statistical software or by comparison with statistical tables. The Mann–Whitney U test effectively considers all pairs of observations from two independent samples and calculates the number of pairs for which an observation in one sample is preceded by an observation from the other. Again, the U statistic can be calculated from the summed ranks within each sample, found by ordering the pooled observations. Such tests depend only on the rank ordering of the observed values and not on any assumptions about their underlying distributions, so that there are no associated parameters to be estimated, and in that sense such methods are considered non-parametric or distribution-free. These are easily implemented in standard statistical software packages such as R, Stata, SAS or SPSS.
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.
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.
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.
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.
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.
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 ≥30 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.
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 90% or
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
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.
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).
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