A Triple Threat: Alcohol Use Disorders in the Presence of Comorbid Chronic Pain Conditions and Depressive Disorders in the Collaborative Psychiatric Epidemiology Surveys, 2001-2003

Background: Frequently patients with chronic pain conditions have comorbid depressive disorders. The relationship between the diagnoses is often bidirectional, with the effects of one condition exacerbating the effects of the other. Alcohol use disorders (AUD) are also independently associated with both conditions. This study aims to determine the prevalence of alcohol use disorders among patients with comorbid chronic pain conditions and depressive disorders in a nationally representative sample of US adults and ascertain the characteristics of patients with all three diagnoses. Methods: This cross-sectional analysis utilizes data from the Collaborative Psychiatric Epidemiology Surveys (CPES), 2001-2003. The sample includes respondents who reported having a chronic pain condition during their lifetime. The outcome is a dichotomous measure of past 12 month AUD, meeting DSM-IV criteria. The exposure is represented as a categorical variable with four groups: no depressive disorder(s) or chronic pain conditions during past year, at least one depressive disorder but no chronic pain conditions during the past year, at least one chronic pain condition during the past year but no depressive disorders during the past year, at least one depressive disorder and at least one chronic pain condition during the past year. Models determining prevalence and patient characteristics were obtained using logistic regression. All analyses account for complex survey design effects. Preliminary Results: Results show an elevated association between having a comorbid chronic pain condition and a depressive disorder and an AUD during the past 12 months, POR=1.914 (0.394, 9.573). This association is not present for the other exposure categories: past year chronic pain but no depressive disorder and past year depressive disorder but no chronic pain. Subsequent models concur after adjusting for potential confounding variables. The prevalence of past year comorbid chronic pain conditions and depressive disorders is 10.93% (SE=0.6931), among adults reporting any chronic pain condition during their lifetime. The prevalence of AUD among adults with comorbid chronic pain and depression is 3.82% (SE=1.132). Discussion: This analysis provides empirical support for the association between psychiatric illness and chronic pain. An association between AUD and comorbid chronic pain and depression signals a need for clinicians to conduct additional screening for AUD when evaluating treatment plans and diagnostic recommendations among adults receiving treatment for chronic pain and depression

Adult Safeguarding and People Living with Dementia in Nursing Homes

While there has been an increased focus on ageing in place in the Irish context, for some people, including people living with dementia (PLWD), nursing home care may be required to adequately meet their care needs as their dementia progresses and care needs increase. Nursing homes are the homes of many PLWD who, despite their frailty and health problems (including dementia), should be supported to enjoy a good quality of life, maintain, and develop relationships, and contribute to society (ADI, 2013).University College DublinIrish Dementia Working Group/AS

Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures

Seizures in neonates, mainly caused by hypoxic-ischemic encephalopathy, are thought to be harmful to the brain. Phenobarbital remains the first line drug therapy for the treatment of suspected neonatal seizures but concerns remain with efficacy and safety. Here we explored the short- and long-term outcomes of phenobarbital treatment in a mouse model of hypoxia-induced neonatal seizures. Seizures were induced in P7 mice by exposure to 5% O-2 for 15 minutes. Immediately after hypoxia, pups received a single dose of phenobarbital (25 mg.kg(-1)) or saline. We observed that after administration of phenobarbital seizure burden and number of seizures were reduced compared to the hypoxic period; however, PhB did not suppress acute histopathology. Behavioural analysis of mice at 5 weeks of age previously subjected to hypoxia-seizures revealed an increase in anxiety-like behaviour and impaired memory function compared to control littermates, and these effects were not normalized by phenobarbital. In a seizure susceptibility test, pups previously exposed to hypoxia, with or without phenobarbital, developed longer and more severe seizures in response to kainic acid injection compared to control mice. Unexpectedly, mice treated with phenobarbital developed less hippocampal damage after kainic acid than untreated counterparts. The present study suggests phenobarbital treatment in immature mice does not improve the long lasting functional deficits induces by hypoxia-induced seizures but, unexpectedly, may reduce neuronal death caused by exposure to a second seizure event in later life

The anti-inflammatory compound candesartan cilexetil improves neurological outcomes in a mouse model of neonatal hypoxia

Recent studies suggest that mild hypoxia-induced neonatal seizures can trigger an acute neuroinflammatory response leading to long-lasting changes in brain excitability along with associated cognitive and behavioral deficits. The cellular elements and signaling pathways underlying neuroinflammation in this setting remain incompletely understood but could yield novel therapeutic targets. Here we show that brief global hypoxia-induced neonatal seizures in mice result in transient cytokine production, a selective expansion of microglia and long-lasting changes to the neuronal structure of pyramidal neurons in the hippocampus. Treatment of neonatal mice after hypoxia-seizures with the novel anti-inflammatory compound candesartan cilexetil suppressed acute seizure-damage and mitigated later-life aggravated seizure responses and hippocampus-dependent learning deficits. Together, these findings improve our understanding of the effects of neonatal seizures and identify potentially novel treatments to protect against short and long-lasting harmful effects

VAST: An ASKAP Survey for Variables and Slow Transients

The Australian Square Kilometre Array Pathfinder (ASKAP) will give us an unprecedented opportunity to investigate the transient sky at radio wavelengths. In this paper we present VAST, an ASKAP survey for Variables and Slow Transients. VAST will exploit the wide-field survey capabilities of ASKAP to enable the discovery and investigation of variable and transient phenomena from the local to the cosmological, including flare stars, intermittent pulsars, X-ray binaries, magnetars, extreme scattering events, interstellar scintillation, radio supernovae and orphan afterglows of gamma ray bursts. In addition, it will allow us to probe unexplored regions of parameter space where new classes of transient sources may be detected. In this paper we review the known radio transient and variable populations and the current results from blind radio surveys. We outline a comprehensive program based on a multi-tiered survey strategy to characterise the radio transient sky through detection and monitoring of transient and variable sources on the ASKAP imaging timescales of five seconds and greater. We also present an analysis of the expected source populations that we will be able to detect with VAST.Comment: 29 pages, 8 figures. Submitted for publication in Pub. Astron. Soc. Australi

A survey and classification of storage deduplication systems

The automatic elimination of duplicate data in a storage system commonly known as deduplication is increasingly accepted as an effective technique to reduce storage costs. Thus, it has been applied to different storage types, including archives and backups, primary storage, within solid state disks, and even to random access memory. Although the general approach to deduplication is shared by all storage types, each poses specific challenges and leads to different trade-offs and solutions. This diversity is often misunderstood, thus underestimating the relevance of new research and development. The first contribution of this paper is a classification of deduplication systems according to six criteria that correspond to key design decisions: granularity, locality, timing, indexing, technique, and scope. This classification identifies and describes the different approaches used for each of them. As a second contribution, we describe which combinations of these design decisions have been proposed and found more useful for challenges in each storage type. Finally, outstanding research challenges and unexplored design points are identified and discussed.This work is funded by the European Regional Development Fund (EDRF) through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT; Portuguese Foundation for Science and Technology) within project RED FCOMP-01-0124-FEDER-010156 and the FCT by PhD scholarship SFRH-BD-71372-2010

Phenobarbital does not worsen outcomes of neonatal hypoxia on hippocampal LTP on rats

IntroductionNeonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been reported to have long-lasting impacts on brain development. For example, in neonatal rodents, HS reduces hippocampal long-term potentiation (LTP), while PB exposure disrupts GABAergic synaptic maturation in the hippocampus. Prior studies have examined the impact of HS and drug treatment separately, but in the clinic, PB is unlikely to be given to neonates without seizures, and neonates with seizures are very likely to receive PB. To address this gap, we assessed the combined and separate impacts of neonatal HS and PB treatment on the development of hippocampal LTP.MethodsMale and female postnatal day (P)7 rat pups were subjected to graded global hypoxia (or normoxia as a control) and treated with either PB (or vehicle as a control). On P13-14 (P13+) or P29-37 (P29+), we recorded LTP of the Schaffer collaterals into CA1 pyramidal layer in acute hippocampal slices. We compared responses to theta burst stimulation (TBS) and tetanization induction protocols.ResultsUnder the TBS induction protocol, female rats showed an LTP impairment caused by HS, which appeared only at P29+. This impairment was delayed compared to male rats. While LTP in HS males was impaired at P13+, it normalized by P29+. Under the tetanization protocol, hypoxia produced larger LTP in males compared to female rats. PB injection, under TBS, did not exacerbate the effects of hypoxia. However, with the tetanization protocol, PB – on the background of HS – compensated for these effects, returning LTP to control levels.DiscussionThese results point to different susceptibility to hypoxia as a function of sex and age, and a non-detrimental effect of PB when administered after hypoxic seizures

Novel computational methods for increasing PCR primer design effectiveness in directed sequencing

<p>Abstract</p> <p>Background</p> <p>Polymerase chain reaction (PCR) is used in directed sequencing for the discovery of novel polymorphisms. As the first step in PCR directed sequencing, effective PCR primer design is crucial for obtaining high-quality sequence data for target regions. Since current computational primer design tools are not fully tuned with stable underlying laboratory protocols, researchers may still be forced to iteratively optimize protocols for failed amplifications after the primers have been ordered. Furthermore, potentially identifiable factors which contribute to PCR failures have yet to be elucidated. This inefficient approach to primer design is further intensified in a high-throughput laboratory, where hundreds of genes may be targeted in one experiment.</p> <p>Results</p> <p>We have developed a fully integrated computational PCR primer design pipeline that plays a key role in our high-throughput directed sequencing pipeline. Investigators may specify target regions defined through a rich set of descriptors, such as Ensembl accessions and arbitrary genomic coordinates. Primer pairs are then selected computationally to produce a minimal amplicon set capable of tiling across the specified target regions. As part of the tiling process, primer pairs are computationally screened to meet the criteria for success with one of two PCR amplification protocols. In the process of improving our sequencing success rate, which currently exceeds 95% for exons, we have discovered novel and accurate computational methods capable of identifying primers that may lead to PCR failures. We reveal the laboratory protocols and their associated, empirically determined computational parameters, as well as describe the novel computational methods which may benefit others in future primer design research.</p> <p>Conclusion</p> <p>The high-throughput PCR primer design pipeline has been very successful in providing the basis for high-quality directed sequencing results and for minimizing costs associated with labor and reprocessing. The modular architecture of the primer design software has made it possible to readily integrate additional primer critique tests based on iterative feedback from the laboratory. As a result, the primer design software, coupled with the laboratory protocols, serves as a powerful tool for low and high-throughput primer design to enable successful directed sequencing.</p

Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. OBJECTIVES: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. METHODS: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. RESULTS: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). CONCLUSIONS: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease