Role of the IL-33/ST2 axis in cardiovascular disease: A systematic review and meta-analysis.

Funder: National Institute of Health Research Cambridge Biomedical Research CentreFunder: AstraZenecaFunder: Cambridge University Hospitals NHS Foundation TrustFunder: British Heart FoundationFunder: National Institute for Health Research (NIHR)UNLABELLED: Interleukin (IL)-33 and its unique receptor, ST2, play a pivotal role in the immune response to infection and stress. However, there have been conflicting reports of the role of IL-33 in cardiovascular disease (CVD) and the potential of this axis in differentiating CVD patients and controls and with CVD disease severity, remains unclear. AIMS: 1) To quantify differences in circulating IL-33 and/or sST2 levels between CVD patients versus controls. 2) Determine association of these biomarkers with mortality in CVD and community cohorts. METHODS AND RESULTS: Using Pubmed/MEDLINE, Web of Science, Prospero and Cochrane databases, systematic review of studies published on IL-33 and/or sST2 levels in patients with CVD (heart failure, acute coronary syndrome, atrial fibrillation, stroke, coronary artery disease and hypertension) vs controls, and in cohorts of each CVD subtype was performed. Pooled standardised mean difference (SMD) of biomarker levels between CVD-cases versus controls and hazard ratios (HRs) for risk of mortality during follow-up in CVD patients, were assessed by random effects meta-analyses. Heterogeneity was evaluated with random-effects meta-regressions. From 1071 studies screened, 77 were meta-analysed. IL-33 levels were lower in HF and CAD patients vs controls, however levels were higher in stroke patients compared controls [Meta-SMD 1.455, 95% CI 0.372-2.537; p = 0.008, I2 = 97.645]. Soluble ST2 had a stronger association with risk of all-cause mortality in ACS (Meta-multivariate HR 2.207, 95% CI 1.160-4.198; p = 0.016, I2 = 95.661) than risk of all-cause mortality in HF (Meta-multivariate HR 1.425, 95% CI 1.268-1.601; p<0.0001, I2 = 92.276). There were insufficient data to examine the association of IL-33 with clinical outcomes in CVD. CONCLUSIONS: IL-33 and sST2 levels differ between CVD patients and controls. Higher levels of sST2 are associated with increased mortality in individuals with CVD. Further study of IL-33/ST2 in cardiovascular studies is essential to progress diagnostic and therapeutic advances related to IL-33/ST2 signalling

A study of the influence of media-based books on independent reading choices

Thesis (M.Ed.) University of Alaska Fairbanks, 2011The purpose of the study was to discover if children's media programming influences the independent reading choices of students. With this purpose in mind, my research was designed to answer the following question: Did children's viewing exposure to the characters, setting, and story format in media-based books provide them with the essential scaffolding necessary to motivate them to read more independently? This project involved approximately 13 fourth grade students, male and female. All of the students have been asked to choose a book to read, fill out a summary sheet for the book, and participate in a reading conference. The researcher has observed the students during the independent reading times, recorded oral retells of the books and conducted interviews with the participants. The results of the study confirmed that students are indeed motivated to read media-based books more independently. It is recommended by the results of this research to offer media-based books for students' independent reading book selection

Society\u27s Views of Law Enforcement Use of Force

Individuals observe their surroundings and naturally judge others by what they observe or hear. In recent media portrayals, law enforcement officers were scrutinized for use of force and individuals were quick to verbalize their interpretation of events. Bandura\u27s social learning theory served as a focal lens to guide the study. This qualitative phenomenological study examined lived experiences and what factors influence public perception of law enforcement use of force. Interviews were conducted with 10 participants who have encountered or witnessed law enforcement officers utilize use of force during a citizen encounter. NVivo software was used to code and analyze themes from interviews. The findings indicated lived experiences and emotions were high and did influence perception of use of force. Participants explained a variety of emotions when discussing their lived experiences. In addition, social media and mainstream news media played an important role in shaping perception of police officer use of force. This study promotes social change by presenting law enforcement agencies and society insight on how to improve on public perception and understanding of use of force so community relationships with law enforcement can flourish

Reproducibility of compartmental modelling of 18 F-FDG PET/CT to evaluate lung inflammation

Abstract: Introduction: Compartmental modelling is an established method of quantifying 18F-FDG uptake; however, only recently has it been applied to evaluate pulmonary inflammation. Implementation of compartmental models remains challenging in the lung, partly due to the low signal-to-noise ratio compared to other organs and the lack of standardisation. Good reproducibility is a key requirement of an imaging biomarker which has yet to be demonstrated in pulmonary compartmental models of 18F-FDG; in this paper, we address this unmet need. Methods: Retrospective subject data were obtained from the EVOLVE observational study: Ten COPD patients (age =66±9; 8M/2F), 10 α1ATD patients (age =63±8; 7M/3F) and 10 healthy volunteers (age =68±8; 9M/1F) never smokers. PET and CT images were co-registered, and whole lung regions were extracted from CT using an automated algorithm; the descending aorta was defined using a manually drawn region. Subsequent stages of the compartmental analysis were performed by two independent operators using (i) a MIAKATTM based pipeline and (ii) an in-house developed pipeline. We evaluated the metabolic rate constant of 18F-FDG (Kim) and the fractional blood volume (Vb); Bland-Altman plots were used to compare the results. Further, we adjusted the in-house pipeline to identify the salient features in the analysis which may help improve the standardisation of this technique in the lung. Results: The initial agreement on a subject level was poor: Bland-Altman coefficients of reproducibility for Kim and Vb were 0.0031 and 0.047 respectively. However, the effect size between the groups (i.e. COPD, α1ATD and healthy subjects) was similar using either pipeline. We identified the key drivers of this difference using an incremental approach: ROI methodology, modelling of the IDIF and time delay estimation. Adjustment of these factors led to improved Bland-Altman coefficients of reproducibility of 0.0015 and 0.027 for Kim and Vb respectively. Conclusions: Despite similar methodology, differences in implementation can lead to disparate results in the outcome parameters. When reporting the outcomes of lung compartmental modelling, we recommend the inclusion of the details of ROI methodology, input function fitting and time delay estimation to improve reproducibility

Surrogate Markers of Cardiovascular Risk and Chronic Obstructive Pulmonary Disease: A Large Case-Controlled Study.

Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid-femoral (aortic) pulse wave velocity, augmentation index, and carotid intima-media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima-media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease

Risk assessment for hospital admission in patients with COPD; a multi-centre UK prospective observational study.

In chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD requiring hospital admission is associated with mortality and healthcare costs. The ERICA study assessed multiple clinical measures in people with COPD, including the short physical performance battery (SPPB), a simple test of physical function with 3 components (gait speed, balance and sit-to-stand). We tested the hypothesis that SPPB score would relate to risk of hospital admissions and length of hospital stay. Data were analysed from 714 of the total 729 participants (434 men and 280 women) with COPD. Data from this prospective observational longitudinal study were obtained from 4 secondary and 1 tertiary centres from England, Scotland, and Wales. The main outcome measures were to estimate the risk of hospitalisation with acute exacerbation of COPD (AECOPD and length of hospital stay derived from hospital episode statistics (HES). In total, 291 of 714 individuals experienced 762 hospitalised AECOPD during five-year follow up. Poorer performance of SPPB was associated with both higher rate (IRR 1.08 per 1 point decrease, 95% CI 1.01 to 1.14) and increased length of stay (IRR 1.18 per 1 point decrease, 95% CI 1.10 to 1.27) for hospitalised AECOPD. For the individual sit-to-stand component of the SPPB, the association was even stronger (IRR 1.14, 95% CI 1.02 to 1.26 for rate and IRR 1.32, 95% CI 1.16 to 1.49 for length of stay for hospitalised AECOPD). The SPPB, and in particular the sit-to-stand component can both evaluate the risk of H-AECOPD and length of hospital stay in COPD. The SPPB can aid in clinical decision making and when prioritising healthcare resources

Correction to: ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial.

An amendment to this paper has been published and can be accessed via the original article

ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial

Abstract: Objectives: Primary objective: To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers. Secondary objectives: To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers. To compare the number of COVID-19 cases between each trial arm on the basis of positive tests (as per current clinical testing methods and/or serology) To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial arm To compare COVID-19 disease severity in each trial arm To compare recovery time from COVID-19 infection in each trial arm Exploratory objectives: To determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive tests To determine if genetic factors determine susceptibility to COVID-19 disease or response to treatment To determine if blood group determines susceptibility to COVID-19 disease To compare serum biomarkers of COVID-19 disease in each arm Trial design: Double-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trial Participants: National Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19. Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19. Inclusion criteria: To be included in the trial the participant MUST: Have given written informed consent to participate Be aged 18 years to 70 years Not previously have been diagnosed with COVID-19 Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care Exclusion criteria: The presence of any of the following will mean participants are ineligible: Known COVID-19 positive test at baseline (if available) Symptomatic for possible COVID-19 at baseline Known hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolines Known retinal disease Known porphyria Known chronic kidney disease (CKD; eGFR<30ml/min) Known epilepsy Known heart failure or conduction problems Known significant liver disease (Gilbert’s syndrome is permitted) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency Currently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, Fluconazole Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine Currently breastfeeding Unable to be followed-up during the trial Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit Not able to use or have access to a modern phone device/web-based technology Any other clinical reason which may preclude entry in the opinion of the investigator Intervention and comparator: Interventions being evaluated are: Daily hydroxychloroquine or Weekly hydroxychloroquine or Placebo The maximum treatment period is approximately 13 weeks per participant. Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight. The dosing regimen for the three arms of the study (A, B, C) are described in further detail below. Arm A: Active Hydroxychloroquine (– daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine:Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine – daily dosing.) Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency: Matched placebo hydroxychloroquine - daily dosing: Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Matched placebo hydroxychloroquine – weekly dosing: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) A schematic of the dosing schedule can be found in the full study protocol (Additional File 1). Main outcomes: Time to diagnosis of positive COVID-19 disease (defined by record of date of symptoms onset and confirmed by laboratory test) Randomisation: Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly. Randomisation will be in a 3:3:2 ratio [hydroxychloroquine-(daily), hydroxychloroquine-(weekly), placebo], using stratified block randomisation. Random block sizes will be used, and stratification will be by study site. Blinding (masking): Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention. Numbers to be randomised (sample size): A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly. Trial Status: V 1.0, 7th April 2020 EU Clinical Trials Register EudraCT Number: 2020-001331-26 Date of registration: 14th April 2020 Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11th May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)

Perspectives on Low Temperature Tolerance and Vernalization Sensitivity in Barley: Prospects for Facultative Growth Habit

One option to achieving greater resiliency for barley production in the face of climate change is to explore the potential of winter and facultative growth habits: for both types, low temperature tolerance (LTT) and vernalization sensitivity are key traits. Sensitivity to short-day photoperiod is a desirable attribute for facultative types. In order to broaden our understanding of the genetics of these phenotypes, we mapped quantitative trait loci (QTLs) and identified candidate genes using a genome-wide association studies (GWAS) panel composed of 882 barley accessions that was genotyped with the Illumina 9K single-nucleotide polymorphism (SNP) chip. Fifteen loci including 5 known and 10 novel QTL/genes were identified for LTT—assessed as winter survival in 10 field tests and mapped using a GWAS meta-analysis. FR-H1, FR-H2, and FR-H3 were major drivers of LTT, and candidate genes were identified for FR-H3. The principal determinants of vernalization sensitivity were VRN-H1, VRN-H2, and PPD-H1. VRN-H2 deletions conferred insensitive or intermediate sensitivity to vernalization. A subset of accessions with maximum LTT were identified as a resource for allele mining and further characterization. Facultative types comprised a small portion of the GWAS panel but may be useful for developing germplasm with this growth habit