Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E−/− model of PAH and atherosclerosis

Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of comorbid atherosclerosis. Apolipoprotein E deficient (ApoE-/-) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD), and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE-/- mice with macitentan, a dual ETA/ETB receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE-/- mice were fed chow or HFD for 8 weeks. After 4 weeks of HFD, mice were randomised to a 4-week treatment of macitentan by food (30mg/kg/day dual ETA/ETB antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterisation were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE-/- mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ETA/ETB receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis

Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients With Advanced Cancer and Bone Metastases Treated With Bone Antiresorptive Agents

Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTMs) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs {greater than or equal to} median vs < median based on month 3 assessments. Results: uNTx levels {greater than or equal to} the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death 1.85, P<0.0001). sBSAP levels {greater than or equal to} median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR 2.44, P<0.0001). uNTx and sBSAP levels {greater than or equal to} median at month 3 were associated with significantly greater risk of DP (HR 1.31, P<0.0001 and HR 1.71, P<0.0001, respectively) and DPB (HR 1.11, P=0.0407 and HR 1.27, P<0.0001, respectively). Conclusions: BTM levels {greater than or equal to} median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes

Kerb and urban increment of highly time-resolved trace elements in PM10, PM2.5 and PM1.0 winter aerosol in London during ClearfLo 2012

Ambient concentrations of trace elements with 2 h time resolution were measured in PM10–2.5, PM2.5–1.0 and PM1.0–0.3 size ranges at kerbside, urban background and rural sites in London during winter 2012. Samples were collected using rotating drum impactors (RDIs) and subsequently analysed with synchrotron radiation-induced X-ray fluorescence spectrometry (SR-XRF). Quantification of kerb and urban increments (defined as kerb-to-urban and urban-to-rural concentration ratios, respectively), and assessment of diurnal and weekly variability provided insight into sources governing urban air quality and the effects of urban micro-environments on human exposure. Traffic-related elements yielded the highest kerb increments, with values in the range of 10.4 to 16.6 for SW winds (3.3–6.9 for NE) observed for elements influenced by brake wear (e.g. Cu, Sb, Ba) and 5.7 to 8.2 for SW (2.6–3.0 for NE) for other traffic-related processes (e.g. Cr, Fe, Zn). Kerb increments for these elements were highest in the PM10–2.5 mass fraction, roughly twice that of the PM1.0–0.3 fraction. These elements also showed the highest urban increments (~ 3.0), although no difference was observed between brake wear and other traffic-related elements. All elements influenced by traffic exhibited higher concentrations during morning and evening rush hours, and on weekdays compared to weekends, with the strongest trends observed at the kerbside site, and additionally enhanced by winds coming directly from the road, consistent with street canyon effects. Elements related to mineral dust (e.g. Al, Si, Ca, Sr) showed significant influences from traffic-induced resuspension, as evidenced by moderate kerb (3.4–5.4 for SW, 1.7–2.3 for NE) and urban (~ 2) increments and increased concentrations during peak traffic flow. Elements related to regional transport showed no significant enhancement at kerb or urban sites, with the exception of PM10–2.5 sea salt (factor of up to 2), which may be influenced by traffic-induced resuspension of sea and/or road salt. Heavy-duty vehicles appeared to have a larger effect than passenger vehicles on the concentrations of all elements influenced by resuspension (including sea salt) and wearing processes. Trace element concentrations in London were influenced by both local and regional sources, with coarse and intermediate fractions dominated by traffic-induced resuspension and wearing processes and fine particles influenced by regional transport

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Longitudinal evaluation of aflatoxin exposure in two cohorts in south-western Uganda

Aflatoxins (AF) are a group of mycotoxins. AF exposure causes acute and chronic adverse health effects such as aflatoxicosis and hepatocellular carcinoma in human populations, especially in the developing world. In this study, AF exposure was evaluated using archived serum samples from human immunodeficiency virus (HIV)-seronegative participants from two cohort studies in south-western Uganda. AFB1-lysine (AFB-Lys) adduct levels were determined via HPLC fluorescence in a total of 713 serum samples from the General Population Cohort (GPC), covering eight time periods between 1989 and 2010. Overall, 90% (642/713) of the samples were positive for AFB-Lys and the median level was 1.58 pg mg(-1) albumin (range = 0.40-168 pg mg(-1) albumin). AFB-Lys adduct levels were also measured in a total of 374 serum samples from the Rakai Community Cohort Study (RCCS), across four time periods between 1999 and 2003. The averaged detection rate was 92.5% (346/374) and the median level was 1.18 pg mg(-1) albumin (range = 0.40-122.5 pg mg(-1) albumin). In the GPC study there were no statistically significant differences between demographic parameters, such as age, sex and level of education, and levels of serum AFB-Lys adduct. In the RCCS study, longitudinal analysis using generalised estimating equations revealed significant differences between the adduct levels and residential areas (p = 0.05) and occupations (p = 0.02). This study indicates that AF exposure in people in two populations in south-western Uganda is persistent and has not significantly changed over time. Data from one study, but not the other, indicated that agriculture workers and rural area residents had more AF exposure than those non-agricultural workers and non-rural area residents. These results suggest the need for further study of AF-induced human adverse health effects, especially the predominant diseases in the region

Screening for Gonorrhea: Recommendation Statement

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all sexually active women, including those who are pregnant, for gonorrhea infection if they are at increased risk for infection (that is, if they are young or have other individual or population risk factors; see Clinical Considerations for further discussion of risk factors). B recommendation

Protocol for validation of the 4AT, a rapid screening tool for delirium: a multicentre prospective diagnostic test accuracy study

INTRODUCTION:Delirium is a severe neuropsychiatric syndrome of rapid onset, commonly precipitated by acute illness. It is common in older people in the emergency department (ED) and acute hospital, but greatly under-recognised in these and other settings. Delirium and other forms of cognitive impairment, particularly dementia, commonly coexist. There is a need for a rapid delirium screening tool that can be administered by a range of professional-level healthcare staff to patients with sensory or functional impairments in a busy clinical environment, which also incorporates general cognitive assessment. We developed the 4 'A's Test (4AT) for this purpose. This study's primary objective is to validate the 4AT against a reference standard. Secondary objectives include (1) comparing the 4AT with another widely used test (the Confusion Assessment Method (CAM)); (2) determining if the 4AT is sensitive to general cognitive impairment; (3) assessing if 4AT scores predict outcomes, including (4) a health economic analysis.METHODS AND ANALYSIS:900 patients aged 70 or over in EDs or acute general medical wards will be recruited in three sites (Edinburgh, Bradford and Sheffield) over 18 months. Each patient will undergo a reference standard delirium assessment and will be randomised to assessment with either the 4AT or the CAM. At 12 weeks, outcomes (length of stay, institutionalisation and mortality) and resource utilisation will be collected by a questionnaire and via the electronic patient record.ETHICS AND DISSEMINATION:Ethical approval was granted in Scotland and England. The study involves administering tests commonly used in clinical practice. The main ethical issues are the essential recruitment of people without capacity. Dissemination is planned via publication in high impact journals, presentation at conferences, social media and the website www.the4AT.com.TRIAL REGISTRATION NUMBER:ISRCTN53388093; Pre-results

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function