Prime mover or fellow traveller:25-hydroxy vitamin D’s seasonal variation, cardiovascular disease and death in the Scottish Heart Health Extended Cohort (SHHEC)

BACKGROUND: Theoretical links between seasonal lack of sunlight, hypovitaminosis D and excess cardiovascular disease and death prompted our adding novel to conventional cohort analyses. METHODS: We tested three postulates on 13 224 Scottish Heart Health Extended Cohort participants, assayed for 25-hydroxyvitamin D (25OHD) and followed for 22 years. (i) Endpoints enumerated by month of occurrence mirror annual seasonal oscillation in 25OHD. (ii) Endpoint seasonality is increased in people with below median 25OHD. (iii) Low 25OHD predicts endpoints independently of major risk factors. RESULTS: Baseline median 25OHD level was 36.4 (other quartiles 26.7, 51.7) nmol/l. The March trough was half the August peak, both well after seasonal solstices. (i) There was no demonstrable monthly variation in First Cardiovascular Event (n = 3307). Peaks and troughs for All Death and Cardiovascular Death (n = 2987, 1350) were near the solstices, earlier than extremes of 25OHD. (ii) Endpoint variability showed no difference between those above and below median 25OHD. (iii) Cox model hazard ratios (HR), by decreasing 25OHD, increased modestly and nonspecifically for all endpoints examined, with no threshold, the gradients diminishing by  ∼ : 60% following multiple adjustment. For Cardiovascular Disease, HR, by 20 (∼SD) nmol/l decrease, = 1.224 (1.175, 1.275) adjusted for age and sex; additionally adjusted for family history, deprivation index, smoking, systolic blood pressure, total and HDL cholesterol, = 1.093 (1.048, 1.139); All Deaths = 1.238 (1.048, 1.139) and 1.098 (1.050, 1.149). 25OHD made no independent contribution to cardiovascular discrimination and reclassification. CONCLUSIONS: Our analyses challenge vitamin D's alleged role as major prime mover in cardiovascular disease and mortality.</p

Evidence of altered epidermal nerve fiber morphology in adults with self-injurious behavior and neurodevelopmental disorders

The purpose of this preliminary study was to examine the morphology and neuropeptide density of epidermal nerve fibers quantified through skin biopsy samples from three adults with neurodevelopmental disorders and chronic self-injurious behavior (SIB) secondary to mental retardation compared with non-SIB normal IQ controls. A cross-sectional design was used with 3 mm punch skin biopsies collected from each participant from non-self-injurious body sites and compared with site-matched existing normal control skin samples. The study was conducted at an outpatient clinic. The primary dependent measure for the morphology analyses was the coefficient of variation (CV) to quantify the mean gap length between epidermal nerve fibers for each subject. Visual microscopic examination and quantitative analysis of the microscopy images suggested there were morphological abnormalities (increased CV) in the epidermal nerve fibers among the chronic SIB cases. Substance P (SP) fiber density was increased with 2 to 3 times as many fibers in SIB subjects as control subjects. Additional empirical work is needed to clarify the relation between sensory innervation of the skin and self-injury to improve assessment and treatment outcomes

Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis:selecting patients for controlled trials of neutrophil elastase inhibition

Background Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. Methods We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for “personalised medicine”. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). Results All three assays showed a high degree of day-to-day variability (0–233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into “high” or “low” groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI −6.0–29.0), sputum colour (β-estimate 10.4, 95% CI 4.3–16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4–11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4–5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for “high” NE (98.7%, 95% CI 7.0–99.6%). Conclusion These results show that patients with bronchiectasis and CF can be effectively divided into “high” or “low” groups, based on sputum NE assays or clinical inclusion criteria

Life In The Cold: An Investigation Of Polar Regions

Polar areas provide unique environments that, though they may seem extreme and uninhabitable, are flourishing with life. These areas around the North and South poles include deep oceans, shallow shelf regions, tundra, mountain ranges and vast glaciers. With the increasing effects of global climate change, a basic knowledge of polar regions is crucial to understand future impacts and implications. The purpose of this book is to give a broad background of polar biology, and also provide details on specific examples through case studies. Topics included throughout this book are: Ice, Life in Polar Regions, Species Interactions, and Anthropogenic Impacts. The students in the Polar Biology course (MAR 464) at the University of New England have researched and reviewed scientific literature to educate readers about these regions. The class, comprised of fourteen junior and senior Marine Science, Ocean Studies and Marine Affairs, and Environmental Sciences students, selected the different topics, presented the material, wrote the chapters, and assembled the final versions into this book. This book cannot be all inclusive, but we think it will provide an excellent broad overview of the most important aspects of Polar Biology and will stimulate the reader to dive into the material further.https://dune.une.edu/marinesci_studproj/1001/thumbnail.jp

A Device to Quantify Sweat in Single Sweat Glands to Diagnose Neuropathy

We devised an objective &quot;Sensitive Sweat Test&quot; (SST) that detects and quantifies early changes in the function of sudomotor nerves that activate sweat glands (SGs). The SST is designed to diagnose peripheral neuropathy early, when the probability for reversal is greatest. Chemotherapy induced and diabetic neuropathy are very common causes of neuropathy in the USA. Both result in peripheral numbness, pain, decreased sweating, abnormal circulation, and eventual weakness. Early recognition can provide a better opportunity to treat and halt neuropathy than discovery after the onset of nerve degeneration. We contend that early diagnosis can be achieved by sensitive monitoring of sweating. Unfortunately, the changes that first signal impending sweat deficiency escape detection by conventional clinical examination and current tests We contracted with several MN small business concerns (SBCs) to construct the SST miniature camera device Methods Skin sites on the medial calf and foot dorsum, each measuring 2 cm 2 were stimulated to sweat maximally by iontophoresis of 1% pilocarpine (2 ma, 5 min; Transparent tape thinly coated with starch was attached over the lens of the SST miniature camera. The skin test sites were prepped with a 1% iodine solution. The skin was wiped dry and immediately the camera was pressed against the skin, activating a switch to begin image collection and storage. As sweat water exited from each sweat pore it contacted iodine and starch and formed a tiny dark spot. The tape prevented formation of a drop. Instead, sweat was forced to flow centrifugally to form a flat expanding dark spot. The SST device imaged spots from &gt;200 SGs at 1 frame/sec (area of 2 cm 2 ) for 60 to 90 seconds, until adjacent spots coalesced. The process was performed twice. Image analysis was done in the Mathworks Software, MATLAB version R2012a. Each individual sweat spot was identified and followed from frame to fram

Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events

AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor. METHODS: A retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c &lt; 48 mmol/mol or &lt;6.5%) diabetes (n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations. RESULTS: In GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p &lt; 0.0001). These effects were replicated in the placebo arm of STABILITY (p &lt; 0.0001). In GoDARTS, stratified analyses showed that, among individuals with poorly controlled diabetes, the hazards of MCE for those with high (Q4) Lp-PLA2 activity was 1.19 compared with individuals with lower (Q1-3) Lp-PLA2 activity (95% CI 1.11, 1.38; p &lt; 0.0001) and 1.35 (95% CI 1.16, 1.57; p &lt; 0.0001) when compared with those with the lowest activity (Q1). Those in the higher risk group were identified as individuals with the highest Lp-PLA2 activity (Q4) and poorly controlled diabetes or diabetes. Based on these observations in untreated populations, we hypothesised that the Lp-PLA2 inhibitor would have more benefit in this higher risk group. In this risk group, Lp-PLA2 inhibitor use was associated with a 33% reduction in MCE compared with placebo (HR 0.67 [95% CI 0.50, 0.90]; p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity. CONCLUSIONS/INTERPRETATION: These results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted. DATA AVAILABILITY: STABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903 . GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease:the BiCARB RCT

Acknowledgements: We would like to acknowledge the support received from the NHS Scotland Support for Science scheme and the NIHR Renal and Ageing Comprehensive Research Networks; the work of all the investigators, research nurses and study teams at the different sites and the Tayside CTU staff; and, most importantly, all those with kidney disease who participated in the trial. In addition, we acknowledge the support and advice that we received from the independent TSC members (Professor David Stott, Professor Patrick Mark, Professor Tahir Masud and Mr Alex Stephen) and the independent DMC members (Professor Alex McConnachie, Professor David Wheeler, Dr Nicosha de Souza and Dr Andrew Clegg). Professor Marion McMurdo and Dr Simon Ogston were co-applicants on the original proposal, but demitted from the project on retirement and were not involved in the creation of this report. Trial registration: Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD

Vitamin K supplementation to improve vascular stiffness in CKD:The K4Kidneys randomized controlled trial

BACKGROUND:Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS:To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS:We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS:Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)