Measurement bias in activation-recovery intervals from unipolar electrograms

The activation-recovery interval (ARI) calculated from unipolar electrograms is regularly used as a convenient surrogate measure of local cardiac action potential durations (APD). This method enables important research bridging between computational studies and in vitro and in vivo human studies. The Wyatt method is well established as a theoretically sound method for calculating ARIs; however, some studies have observed that it is prone to a bias error in measurement when applied to positive T waves. This article demonstrates that recent theoretical and computational studies supporting the use of the Wyatt method are likely to have underestimated the extent of this bias in many practical experimental recording scenarios. This work addresses these situations and explains the measurement bias by adapting existing theoretical expressions of the electrogram to represent practical experimental recording configurations. A new analytic expression for the electrogram's local component is derived, which identifies the source of measurement bias for positive T waves. A computer implementation of the new analytic model confirms our hypothesis that the bias is systematically dependent on the electrode configuration. These results provide an aid to electrogram interpretation in general, and this work's outcomes are used to make recommendations on how to minimize measurement error

IMPLEmenting a clinical practice guideline for acute low back pain evidence-based manageMENT in general practice (IMPLEMENT) : cluster randomised controlled trial study protocol

Background: Evidence generated from reliable research is not frequently implemented into clinical practice. Evidence-based clinical practice guidelines are a potential vehicle to achieve this. A recent systematic review of implementation strategies of guideline dissemination concluded that there was a lack of evidence regarding effective strategies to promote the uptake of guidelines. Recommendations from this review, and other studies, have suggested the use of interventions that are theoretically based because these may be more effective than those that are not. An evidencebased clinical practice guideline for the management of acute low back pain was recently developed in Australia. This provides an opportunity to develop and test a theory-based implementation intervention for a condition which is common, has a high burden, and for which there is an evidence-practice gap in the primary care setting. Aim: This study aims to test the effectiveness of a theory-based intervention for implementing a clinical practice guideline for acute low back pain in general practice in Victoria, Australia. Specifically, our primary objectives are to establish if the intervention is effective in reducing the percentage of patients who are referred for a plain x-ray, and improving mean level of disability for patients three months post-consultation. Methods/Design: This study protocol describes the details of a cluster randomised controlled trial. Ninety-two general practices (clusters), which include at least one consenting general practitioner, will be randomised to an intervention or control arm using restricted randomisation. Patients aged 18 years or older who visit a participating practitioner for acute non-specific low back pain of less than three months duration will be eligible for inclusion. An average of twenty-five patients per general practice will be recruited, providing a total of 2,300 patient participants. General practitioners in the control arm will receive access to the guideline using the existing dissemination strategy. Practitioners in the intervention arm will be invited to participate in facilitated face-to-face workshops that have been underpinned by behavioural theory. Investigators (not involved in the delivery of the intervention), patients, outcome assessors and the study statistician will be blinded to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012606000098538 (date registered 14/03/2006).The trial is funded by the NHMRC by way of a Primary Health Care Project Grant (334060). JF has 50% of her time funded by the Chief Scientist Office3/2006). of the Scottish Government Health Directorate and 50% by the University of Aberdeen. PK is supported by a NHMRC Health Professional Fellowship (384366) and RB by a NHMRC Practitioner Fellowship (334010). JG holds a Canada Research Chair in Health Knowledge Transfer and Uptake. All other authors are funded by their own institutions

Graft calcifications and dysfunction following liver transplantation

BACKGROUND: The molecular events, following ischemia and reperfusion (I/R) of the liver during transplantation are largely unknown. There is evidence that apoptotic and necrotic events may take place, and occasionally result in primary graft dysfunction. We herein report two cases, where significant I/R injury correlated with the development of liver calcification and primary liver dysfunction. CASE PRESENTATION: Both patients with clinical and biochemical evidence of primary graft dysfunction demonstrated calcification at light and electron microscopy levels. In addition, one patient had macroscopic evidence of calcification on cross-sectional imaging. Both patients died secondary to the sequelae of the graft dysfunction. CONCLUSIONS: Severe I/R-induced injury to the liver, clinically leads to graft dysfunction. This is due to advanced apoptotic and/or necrotic events at the hepatocyte level that may, on the most severe form, lead to calcification. The study of microcalcification at the early posttransplant period could provide insight in the events taking place following significant ischemia/reperfusion-induced injury to the graft

Exploring C semantics and pointer provenance

The semantics of pointers and memory objects in C has been a vexed question for many years. C values cannot be treated as either purely abstract or purely concrete entities: the language exposes their representations, but compiler optimisations rely on analyses that reason about provenance and initialisation status, not just runtime representations. The ISO WG14 standard leaves much of this unclear, and in some respects differs with de facto standard usage - which itself is difficult to investigate. In this paper we explore the possible source-language semantics for memory objects and pointers, in ISO C and in C as it is used and implemented in practice, focussing especially on pointer provenance. We aim to, as far as possible, reconcile the ISO C standard, mainstream compiler behaviour, and the semantics relied on by the corpus of existing C code. We present two coherent proposals, tracking provenance via integers and not; both address many design questions. We highlight some pros and cons and open questions, and illustrate the discussion with a library of test cases. We make our semantics executable as a test oracle, integrating it with the Cerberus semantics for much of the rest of C, which we have made substantially more complete and robust, and equipped with a web-interface GUI. This allows us to experimentally assess our proposals on those test cases. To assess their viability with respect to larger bodies of C code, we analyse the changes required and the resulting behaviour for a port of FreeBSD to CHERI, a research architecture supporting hardware capabilities, which (roughly speaking) traps on the memory safety violations which our proposals deem undefined behaviour. We also develop a new runtime instrumentation tool to detect possible provenance violations in normal C code, and apply it to some of the SPEC benchmarks. We compare our proposal with a source-language variant of the twin-allocation LLVM semantics proposal of Lee et al. Finally, we describe ongoing interactions with WG14, exploring how our proposals could be incorporated into the ISO standard

Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

<p>Abstract</p> <p>Background</p> <p>The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only.</p> <p>Methods/Design</p> <p>This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis.</p> <p>Discussion</p> <p>This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions.</p

The use of tumour necrosis factor alpha-blockers in daily routine. An Austrian consensus project

To define relevant disease parameters and their respective limits indicating the initiation of TNF-α-blockers in individual patients. Subsequently, to analyze retrospectively patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), who started TNF-α inhibition in 2006. Points to consider, regarded relevant for individual treatment decisions as well as their assessment methods, were ascertained by experts’ consensus applying the Delphi technique. Subsequently, these parameters’ thresholds with respect to the initiation of a TNF-α-blocker were identified. Thereafter, the rheumatologists representing 12 centres all over Austria agreed to retrospectively analyze their patients started on a TNF-α-blocker in 2006. Experts’ opinion regarding disease parameters relevant to initiate TNF-α-blockers in RA patients only slightly differed from those applied in clinical trials, but the parameters’ threshold values were considerably lower. For PsA patients, some differences and for AS patients, considerable differences between experts’ opinion and clinical studies appeared, which held also true for decisive parameters’ means and thresholds. Six hundred and fifty patients, started on TNF-blockers in 2006, could be analyzed retrospectively, 408 RA patients (53.3 years mean, 340 females), 93 PsA patients (48.9 years mean, 59 males) and 149 AS patients AS (42.2 years mean, 108 males), representing approximately 25% of all Austrian patients initiated on a TNF-blocker in this respective year. Far more individualized, patient-oriented treatment approaches, at least in part, are applied in daily routine compared with those derived from clinical trials or recommendations from investigative rheumatologists

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Thyroid function in Danish greenhouse workers

BACKGROUND: From animal studies it is known that currently used pesticides can disturb thyroid function. METHODS: In the present study we investigated the thyroid function in 122 Danish greenhouse workers, to evaluate if greenhouse workers classified as highly exposed to pesticides experiences altered thyroid levels compared to greenhouse workers with lower exposure. Serum samples from the greenhouse workers were sampled both in the spring and the fall to evaluate if differences in pesticide use between seasons resulted in altered thyroid hormone levels. RESULTS: We found a moderate reduction of free thyroxine (FT4) (10–16%) among the persons working in greenhouses with a high spraying load both in samples collected in the spring and the fall, but none of the other measured thyroid hormones differed significantly between exposure groups in the cross-sectional comparisons. However, in longitudinal analysis of the individual thyroid hormone level between the spring and the fall, more pronounced differences where found with on average 32% higher thyroid stimulating hormone (TSH) level in the spring compared to the fall and at the same time a 5–9% lower total triiodthyroxin (TT3), free triiodthyroxine (FT3) and FT4. The difference between seasons was not consistently more pronounced in the group classified as high exposure compared to the low exposure groups. CONCLUSION: The present study indicates that pesticide exposure among Danish greenhouse workers results in only minor disturbances of thyroid hormone levels

Behavioral Inhibition and Attentional Control in Adolescents: Robust Relationships with Anxiety and Depression

Behavioral inhibition (BI) has been associated with the development of internalizing disorders in children and adolescents. It has further been shown that attentional control (AC) is negatively associated with internalizing problems. The combination of high BI and low AC may particularly lead to elevated symptomatology of internalizing behavior. This study broadens existing knowledge by investigating the additive and interacting effects of BI and AC on the various DSM-IV based internalizing dimensions. A sample of non-clinical adolescents (N = 1806, age M = 13.6 years), completed the Behavioral Inhibition System/Behavioral Activation System Scales (BIS/BAS), the attentional control subscale of the Adult Temperament Questionnaire (ATQ) and the Revised Child Anxiety and Depression Scale (RCADS). As expected, BI was positively, and AC was negatively related to internalizing dimensions, with stronger associations of BI than of AC with anxiety symptoms, and a stronger association of AC than of BI with depressive symptoms. AC moderated the association between BI and all measured internalizing dimensions (i.e., symptoms of generalized anxiety disorder, social phobia, separation anxiety disorder, panic disorder, obsessive–compulsive disorder, and major depressive disorder). Since high AC may reduce the impact of high BI on the generation of internalizing symptoms, an intervention focused on changing AC may have potential for prevention and treatment of internalizing disorders