Elevated ACKR2 expression is a common feature of inflammatory arthropathies

Objectives. Chemokines are essential contributors to leucocyte accumulation at sites of inflammatory pathology. Interfering with chemokine or chemokine receptor function therefore represents a plausible therapeutic option. However, our currently limited understanding of chemokine orchestration of inflammatory responses means that such therapies have not yet been fully developed. We have a particular interest in the family of atypical chemokine receptors that fine-tune, or resolve, chemokine-driven responses. In particular we are interested in atypical chemokine receptor 2 (ACKR2), which is a scavenging receptor for inflammatory CC-chemokines and that therefore helps to resolve in vivo inflammatory responses. The objective of the current study was to examine ACKR2 expression in common arthropathies. Methods. ACKR2 expression was measured by a combination of qPCR and immuno-histochemistry. In addition, circulating cytokine and chemokine levels in patient plasma were assessed using multiplexing approaches. Results. Expression of ACKR2 was elevated on peripheral blood cells as well as on leucocytes and stromal cells in synovial tissue. Expression on peripheral blood leucocytes correlated with, and could be regulated by, circulating cytokines with particularly strong associations being seen with IL-6 and hepatocyte growth factor. In addition, expression within the synovium was coincident with aggregates of lymphocytes, potentially atopic follicles and sites of high inflammatory chemokine expression. Similarly increased levels of ACKR2 have been reported in psoriasis and SSc. Conclusion. Our data clearly show increased ACKR2 in a variety of arthropathies and taking into account our, and others’, previous data we now propose that elevated ACKR2 expression is a common feature of inflammatory pathologies

GaPP: a pilot randomised controlled trial of the efficacy of action of gabapentin for the management of chronic pelvic pain in women: study protocol

<p><b>Introduction:</b> Chronic pelvic pain (CPP) affects >1 million UK women. Annual healthcare costs are estimated at >£150 million. Proven interventions for CPP are limited, and treatment is often unsatisfactory. Gabapentin is increasingly prescribed due to reports of effectiveness in other chronic pain conditions, but there are insufficient data supporting value in CPP specifically. The mechanism by which gabapentin exerts its analgesic action is unknown. Given the prevalence and costs of CPP, the authors believe that a large, multicentre, placebo-controlled, double-blind randomised controlled trial to evaluate the efficacy of gabapentin in management of CPP is required. The focus of this study is a pilot to inform planning of a future randomised controlled trial.</p> <p><b>Methods and analysis:</b> The authors plan to perform a two-arm, parallel, randomised controlled pilot trial. The authors aim to recruit 60 women with CPP in NHS Lothian and NHS Grampian (UK) and randomise them to gabapentin or placebo. Response to treatment will be monitored by questionnaire compared at 0, 3 and 6 months. The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness and acceptability to participants of the proposed methods of recruitment, randomisation, drug treatments and assessment tools and to perform a pretrial cost-effectiveness assessment of treatment with gabapentin.</p> <p><b>Ethics and dissemination:</b> Ethical approval has been obtained from the Scotland A Research Ethics Committee (LREC 12/SS/0005). Data will be presented at international conferences and published in peer-reviewed journals.</p&gt

Three Dimensional Quantification of Angiotensin II-Induced Murine Abdominal Aortic Aneurysms Using High Frequency Ultrasound

Abdominal aortic aneurysms (AAAs), a localized dilation of the vessel wall of 50% or more above normal, claims approximately 14,000 U.S. lives yearly due to aortic rupture. This commonly asymptomatic disease can only be treated by endovascular stent grafts or invasive surgery, usually after the AAA diameter reaches 5 cm. Because these treatment methods carry serious risk, stem cell therapy is being explored in order to provide a low risk option for managing smaller AAAs. To determine if stem cell therapy, once administered, could stabilize or reduce AAA growth, baseline 3D ultrasound measurements in a control group were first needed. High frequency ultrasound was used on apolipoprotein E-deficient (apoE-/-) mice given angiotensin II (AngII) from subcutaneously implanted osmotic mini pumps. This mouse model developed dissecting AAAs, containing a false and true lumen, which were clearly visualized and quantified using 3D ultrasound imaging. With this ultrasound technique, we found that aneurysm diameter, total volume, and false lumen volume all increased steadily over a period of 28 days once AAAs formed. These data suggest our noninvasive, 3D ultrasound technique can be used to monitor the progression of aneurysms that may be delayed once stem cell therapy is administered

Nonlinear Optical Microscopy of Murine Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by dilation and weakening of the vessel wall. AAA rupture is responsible for approximately 14,000 deaths annually in the United States [1]. Nonlinear optical (NLO) microscopy presents new possibilities for analyzing AAA tissue samples from murine models. Common NLO techniques are two-photon excitation fluorescence (TPEF), which detects the intrinsic autofluorescent properties of elastin, and second-harmonic generation (SHG), which is specific for collagen fibrils. Elastin and collagen, two major extracellular matrix components, help the aortic wall withstand internal pressure. Murine AAAs were created through 1) subcutaneous continuous systemic infusion of angiotensin II (AngII) in hyperlipidemic apolipoprotein E-deficient mice and 2) by intraluminal infusion of elastase (low 0.5 U/ml and high 25 U/ml concentrations) into the infrarenal aorta of rats [2]. We imaged aneurysmal and control tissue using TPEF and SHG and compared the resulting images to sections stained with standard elastin and collagen markers. TPEF images revealed disorganized elastin sheets and SHG images indicated collagen turnover after aneurysm formation. We quantified the relative degree of elastin degradation and collagen content in the aortic media within a user-defined area on sections stained with Verhoeff-van Gieson (VVG) or Masson’s trichrome (MTC), as well as on TPEF and SHG images. Our analysis with VVG-stained sections shows that elastin content in AAA tissue is significantly decreased by 64% in AngII models (P=0.02), by 34% in low concentration elastase models (P=0.07), and by 99% in high concentration elastase models (P=0.03), relative to control aortic tissue

Predicting asthma-related crisis events using routine electronic healthcare data

Background There is no published algorithm predicting asthma crisis events (accident and emergency [A&E] attendance, hospitalisation, or death) using routinely available electronic health record (EHR) data. Aim To develop an algorithm to identify individuals at high risk of an asthma crisis event. Design and setting Database analysis from primary care EHRs of people with asthma across England and Scotland. Method Multivariable logistic regression was applied to a dataset of 61 861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage Databank of 174 240 patients from Wales. Outcomes were ≥1 hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance, or death (validation dataset) within a 12-month period. Results Risk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking, and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a receiver operating characteristic of 0.71 (95% confidence interval [CI] = 0.70 to 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI = 5.3% to 6.1%) and a negative predictive value of 98.9% (95% CI = 98.9% to 99.0%), with sensitivity of 28.5% (95% CI = 26.7% to 30.3%) and specificity of 93.3% (95% CI = 93.2% to 93.4%); those individuals had an event risk of 6.0% compared with 1.1% for the remaining population. In total, 18 people would need to be followed to identify one admission. Conclusion This externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding those not at high risk

Injuries, Ill-Health and Fatalities in White Water Rafting and White Water Paddling

White water (WW) activities such as paddling (canoeing and kayaking) and rafting are popular sports for recreational and professional participants. An increase in participation has been seen worldwide. However, these activities come with a risk of injury and even death if not conducted safely. A review was conducted to identify the types of injuries and ill-health that occur as a result of these activities. Injury and fatality rates were assessed to establish the risk attributed to these activities. Web of Science, PubMed, Ergonomics Abstracts and PsycINFO databases were searched and a total of 16 published articles were identified and reviewed. The shoulders and back were the most vulnerable sites for injury in WW paddling. Injuries to the face and lower limbs were most common in WW rafters. However, injury rates are low and estimates are discussed. Due to different methods used across the studies, the reported injury rates are not comparable. This review identified three illnesses incurred through WW activities. There may be more but these are not currently reported in the literature. A relative paucity of studies regarding injuries and fatalities in WW activities was identified. Directions for future research are suggested and discussed

Protocol for a systematic review to identify and weight the indicators of risk of asthma exacerbations in children aged 5-12 years

No abstract available

GaPP: a pilot randomised controlled trial of the efficacy of action of gabapentin for the management of chronic pelvic pain in women: study protocol

ABSTRACT Introduction: Chronic pelvic pain (CPP) affects >1 million UK women. Annual healthcare costs are estimated at >£150 million. Proven interventions for CPP are limited, and treatment is often unsatisfactory. Gabapentin is increasingly prescribed due to reports of effectiveness in other chronic pain conditions, but there are insufficient data supporting value in CPP specifically. The mechanism by which gabapentin exerts its analgesic action is unknown. Given the prevalence and costs of CPP, the authors believe that a large, multicentre, placebo-controlled, double-blind randomised controlled trial to evaluate the efficacy of gabapentin in management of CPP is required. The focus of this study is a pilot to inform planning of a future randomised controlled trial. Methods and analysis: The authors plan to perform a two-arm, parallel, randomised controlled pilot trial. The authors aim to recruit 60 women with CPP in NHS Lothian and NHS Grampian (UK) and randomise them to gabapentin or placebo. Response to treatment will be monitored by questionnaire compared at 0, 3 and 6 months. The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness and acceptability to participants of the proposed methods of recruitment, randomisation, drug treatments and assessment tools and to perform a pretrial costeffectiveness assessment of treatment with gabapentin

Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1): A Pilot Randomised Controlled Trial

Chronic pelvic pain (CPP) affects 2.1–24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women’s experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012–2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07–3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97–6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial

Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: A cohort study in Ontario, Canada

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort. Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence. Results: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined. Conclusions: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age