A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.     

A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study)

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81–11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients.     

Brain systems mediating semantic and syntactic processing in deaf native signers: Biological invariance and modality specificity

Studies of written and spoken language suggest that nonidentical brain networks support semantic and syntactic processing. Event-related brain potential (ERP) studies of spoken and written languages show that semantic anomalies elicit a posterior bilateral N400, whereas syntactic anomalies elicit a left anterior negativity, followed by a broadly distributed late positivity. The present study assessed whether these ERP indicators index the activity of language systems specific for the processing of aural-oral language or if they index neural systems underlying any natural language, including sign language. The syntax of a signed language is mediated through space. Thus the question arises of whether the comprehension of a signed language requires neural systems specific for this kind of code. Deaf native users of American Sign Language (ASL) were presented signed sentences that were either correct or that contained either a semantic or a syntactic error (1 of 2 types of verb agreement errors). ASL sentences were presented at the natural rate of signing, while the electroencephalogram was recorded. As predicted on the basis of earlier studies, an N400 was elicited by semantic violations. In addition, signed syntactic violations elicited an early frontal negativity and a later posterior positivity. Crucially, the distribution of the anterior negativity varied as a function of the type of syntactic violation, suggesting a unique involvement of spatial processing in signed syntax. Together, these findings suggest that biological constraints and experience shape the development of neural systems important for language.     

Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence

Reactive oxygen species (ROS) appear to play a role in limiting both cellular and organismic lifespan. However, because of their pleiotropic effects, it has been difficult to ascribe a specific role to ROS in initiating the process of cellular senescence. We have studied the effects of oxidative DNA damage on cell proliferation, believing that such damage is of central importance to triggering senescence. To do so, we devised a strategy to decouple levels of 8-oxoguanine, a major oxidative DNA lesion, from ROS levels. Suppression of MTH1 expression, which hydrolyzes 8-oxo-dGTP, was accompanied by increased total cellular 8-oxoguanine levels and caused early-passage primary and telomerase-immortalized human skin fibroblasts to rapidly undergo senescence, doing so without altering cellular ROS levels. This senescent phenotype recapitulated several salient features of replicative senescence, notably the presence of senescence-associated beta-galactosidase (SA beta-gal) activity, apparently irreparable genomic DNA breaks, and elevation of p21^Cip1, p53, and p16^INK4A tumor suppressor protein levels. Culturing cells under low oxygen tension (3%) largely prevented the shMTH1-dependent senescent phenotype. These results indicate that the nucleotide pool is a critical target of intracellular ROS and that oxidized nucleotides, unless continuously eliminated, can rapidly induce cell senescence through signaling pathways very similar to those activated during replicative senescence.     

Predictors and Outcomes of Frequent Emergency Department Users

OBJECTIVE: To identify predictors and outcomes associated with frequent emergency department (ED) users. METHODS: Cross-sectional intake surveys, medical chart reviews, and telephone follow-up interviews of patients presenting with selected chief complaints were performed at five urban EDs during a one-month study period in 1995. Frequent use was defined by four or more self-reported, prior ED visits. Multivariate logistic regression identified predictors of frequent ED visitors from five domains (demographics, health status, health access, health care preference, and severity of acute illness). Associations between high use and selected outcomes were assessed with logistic regression models. RESULTS: All study components were completed by 2,333 of 3,455 eligible patients (67.5%). Demographics predicting frequent use included being a single parent, single or divorced marital status, high school education or less, and income of less than $10,000 (1995). Health status predictors included hospitalization in the preceding three months, high ratings of psychological distress, and asthma. Health access predictors included identifying an ED or a hospital clinic as the primary care site, having a primary care physician (PCP), and visiting a PCP in the past month. Choosing the ED for free care was the only health preference predictive of heavy use. Illness severity measures were higher in frequent visitors, although these were not independently predictive in the multivariate model. Outcomes correlated with heavy use include increased hospital admissions, higher rates of ED return visits, and lower patient satisfaction, but not willingness to return to the ED or follow-up with a doctor. CONCLUSIONS: Frequent ED visits are associated with socioeconomic distress, chronic illness, and high use of other health resources. Efforts to reduce ED visits require addressing the unique needs of these patients in the emergency and primary care settings.     

Ex vivo synergy of arachidonate-enriched serum with ceftazidime and amikacin on multidrug-resistant Pseudomonas aeruginosa

Three multidrug-resistant strains of Pseudomonas aeruginosa were incubated ex vivo with sera sampled after a 10 min intravenous infusion of 25 mg/kg of arachidonic acid (AA) in 10 rabbits in the presence of ceftazidime and amikacin. Lipid peroxidation was assessed during bacterial growth. A statistically significant decrease in bacterial cells was found by the interaction of antimicrobials and serum sampled in the middle of infusion and 15 and 30 min after infusion of AA and was accompanied by elevated levels of malonodialdehyde. This effect of AA is probably attributed to lipid peroxidation and raises the possibility of its application in experimental infections.