Orexin/hypocretin role in reward: implications for opioid and other addictions

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the ‘anti-reward’ effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.

Surveillance snapshot of Clostridium difficile infection in hospitals across Queensland detects binary toxin producing ribotype UK 244

In North America and Europe, the binary toxin positive Clostridium difficile strains of the ribotypes 027 and 078 have been associated with death, toxic megacolon and other adverse outcomes. Following an increase in C. difficile infections (CDIs) in Queensland, a prevalence study involving 175 hospitals was undertaken in early 2012, identifying 168 cases of CDI over a 2 month period. Patient demographics and clinical characteristics were recorded, and C. difficile isolates were ribotyped and tested for the presence of binary toxin genes. Most patients (106/168, 63.1%) were aged over 60 years. Overall, 98 (58.3%) developed symptoms after hospitalisation; 89 cases (53.0%) developed symptoms more than 48 hours after admission. Furthermore, 27 of the 62 (67.7%) patients who developed symptoms in the community ad been hospitalised within the last 3 months. Thirteen of the 168 (7.7%) cases identified had severe disease, resulting in admission to the Intensive Care Unit or death within 30 days of the onset of symptoms. The 3 most common ribotypes isolated were UK 002 (22.9%), UK 014 (13.3%) and the binary toxin-positive ribotype UK 244 (8.4%). The only other binary toxin positive ribotype isolated was UK 078 (n = 1). Of concern was the detection of the binary toxin positive ribotype UK 244, which has recently been described in other parts of Australia and New Zealand. No isolates were of the international epidemic clone of ribotype UK 027, although ribotype UK 244 is genetically related to this clone. Further studies are required to track the epidemiology of ribotype UK 244 in Australia and New Zealand. Commun Dis Intell 2014;38(4):E279–E284.

Potentially inappropriate prescribing in older patients admitted to acute care hospitals and discharged to residential aged care facilities

Background The frequency of prescribing potentially inappropriate medications (PIMs) in older patients remains high regardless of the evidence of adverse outcomes from their use. This study aims to identify the prevalence and nature of PIMs at admission to acute care and at discharge to residential aged care facilities (RACFs) using the recently updated Beers’ Criteria. We also aim to identify if polypharmacy, age, gender and the frailty status of patients are independent risk factors for receiving a PIM. Methods This was a retrospective study of 206 patients discharged to RACFs from acute care. All patients were aged at least70 years and were admitted between July 2005 and May 2010; their admission and discharge medications were evaluated. Frailty status was measured as the Frailty Index (FI), adding each individual’s deficits and dividing by the total number of deficits considered, with FI 0.25 used as the cut-off between “fit” and “frail”. Results Mean patient age was 84.8 ± 6.7 years; the majority (57%) were older than 85 years and approximately 90% were frail. Patients were prescribed a mean of 7.2 regular medications at admission and 8.1 on discharge. At least one PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge. Of all medications prescribed at admission (1728), 10.8% were PIMs and at discharge of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 were continued; 32 new PIMs were introduced. Commonly prescribed PIMs at both admission and discharge were central nervous system, cardiovascular and gastrointestinal drugs and analgesics. Of the potential risk factors, frailty status was the only significant predictor of PIMs at both admission and discharge (p = 0.016). Conclusion A high prevalence of unnecessary drug use was observed in frail older patients on admission to acute care hospitals and on discharge to RACFs. The only association with PIM use was the frailty status of patients. Further studies are needed to further evaluate this association.

The impact of frailty and polypharmacy on adverse outcomes in older inpatients

Background Older people are at significant risk of adverse outcomes as a result of changes in physiology, frailty, co-morbidity and polypharmacy.1 Timely identification of high-risk patients may facilitate the optimization of medication and reduce the incidence of adverse outcomes. The aims of this study were to evaluate in older inpatients the relationships between risk factors, including frailty and polypharmacy, and adverse health outcomes. Methods This is a prospective study of 1418 patients, aged 70 and older, admitted to general medical units in 11 acute care hospitals across Australia. The interRAI Acute Care (interRAI AC) assessment tool was used for data collection. Frailty status was measured using a Frailty Index (FI), adding each individual’s deficits and dividing by the total number of deficits considered. Adverse health outcomes included falls in hospital, delirium, in-hospital functional and cognitive decline, discharge to a higher level of care and inpatient mortality. Results Patients had a mean age 81 ± 6.8 years with a median length of hospital stay of 6 days (interquartile range 4 to 11 days); 701 (50%) experienced at least one adverse outcome. Polypharmacy (5-9 drugs per day) was observed in almost half of the study population (n=695, 49%) and hyper-polypharmacy (≥10 drugs) observed in about one-third of patients (n=490, 34.6%). Cognitive impairment was shown to be associated with the lower rate of prescribing. FI had a significant association with all adverse outcomes studied (p = <0.05). In contrast, no association was observed between polypharmacy categories and adverse outcomes except for those on 10 or more drugs where they were more likely to be discharged to a higher level of care (p= 0.014). Conclusions Among older inpatients, frailty status was a significant predictor of adverse outcomes. Lower rates of prescribing to patients with cognitive impairment may underpin the lack of an association between polypharmacy and adverse outcomes in this cohort. References: 1. Olsson IN, Runnamo R, Engfeldt P. Medication quality and quality of life in the elderly, a cohort study.Health Qual Life Outcomes.2011;9:95

Mitochondrial membrane potential in a small subset of artemisinin-induced dormant plasmodium falciparum parasites in vitro

Artemisinin induced dormancy is a proposed mechanism for failures of mono-therapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that following dihydroartemisinin (DHA) treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential (MMP) marker, and persisted to recovery. FACS sorted RH-positive parasites resumed growth at 10,000/well while RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was only detected in RH-positive dormant parasites. Importantly, after treating dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.

Functional neuroanatomy of auditory mismatch processing : an event-related fMRI study of duration-deviant oddballs

This study was designed to identify the neural networks underlying automatic auditory deviance detection in 10 healthy subjects using functional magnetic resonance imaging. We measured blood oxygenation level-dependent contrasts derived from the comparison of blocks of stimuli presented as a series of standard tones (50 ms duration) alone versus blocks that contained rare duration-deviant tones (100 ms) that were interspersed among a series of frequent standard tones while subjects were watching a silent movie. Possible effects of scanner noise were assessed by a “no tone” condition. In line with previous positron emission tomography and EEG source modeling studies, we found temporal lobe and prefrontal cortical activation that was associated with auditory duration mismatch processing. Data were also analyzed employing an event-related hemodynamic response model, which confirmed activation in response to duration-deviant tones bilaterally in the superior temporal gyrus and prefrontally in the right inferior and middle frontal gyri. In line with previous electrophysiological reports, mismatch activation of these brain regions was significantly correlated with age. These findings suggest a close relationship of the event-related hemodynamic response pattern with the corresponding electrophysiological activity underlying the event-related “mismatch negativity” potential, a putative measure of auditory sensory memory.

Functional brain maps of Tower of London performance : a positron emission tomography and functional magnetic resonance imaging study

Regional cerebral blood flow (rCBF) and blood oxygenation level-dependent (BOLD) contrasts represent different physiological measures of brain activation. The present study aimed to compare two functional brain imaging techniques (functional magnetic resonance imaging versus [15O] positron emission tomography) when using Tower of London (TOL) problems as the activation task. A categorical analysis (task versus baseline) revealed a significant BOLD increase bilaterally for the dorsolateral prefrontal and inferior parietal cortex and for the cerebellum. A parametric haemodynamic response model (or regression analysis) confirmed a task-difficulty-dependent increase of BOLD and rCBF for the cerebellum and the left dorsolateral prefrontal cortex. In line with previous studies, a task-difficulty-dependent increase of left-hemispheric rCBF was also detected for the premotor cortex, cingulate, precuneus, and globus pallidus. These results imply consistency across the two neuroimaging modalities, particularly for the assessment of prefrontal brain function when using a parametric TOL adaptation.

The Long and Short of It: Branch Lengths and the Problem of Placing the New Zealand Short-Tailed Bat, Mystacina

The taxonomic position of the endemic New Zealand bat genus Mystacina has vexed systematists ever since its erection in 1843. Over the years the genus has been linked with many microchiropteran families and superfamilies. Most recent classifications place it in the Vespertilionoidea, although some immunological evidence links it with the Noctilionoidea (=Phyllostomoidea). We have sequenced 402 bp of the mitochondrial cytochrome b gene for M. tuberculata (Gray in Dieffenbach, 1843), and using both our own and published DNA sequences for taxa in both superfamilies, we applied different tree reconstruction methods to find the appropriate phylogeny and different methods of estimating confidence in the parts of the tree. All methods strongly support the classification of Mystacina in the Noctilionoidea. Spectral analysis suggests that parsimony analysis may be misleading for Mystacina's precise placement within the Noctilionoidea because of its long terminal branch. Analyses not susceptible to long-branch attraction suggest that the Mystacinidae is a sister family to the Phyllostomidae. Dating the divergence times between the different taxa suggests that the extant chiropteran families radiated around and shortly after the Cretaceous-Tertiary boundary. We discuss the biogeographical implications of classifying Mystacina within the Noctilionoidea and contrast our result with those classifications placing Mystacina in the Vespertilionoidea, concluding that evidence for the latter is weak.

The origin of cyclical high- and low-Cr basalts with continental crust trace element signatures in the Kalkarindji Large Igneous Province

The 510 million year old Kalkarindji Large Igneous Province correlates in time with the first major extinction event after the Cambrian explosion of life. Large igneous provinces correlate with all major mass extinction events in the last 500 million years. The genetic link between large igneous provinces and mass extinction remains unclear. My work is a contribution towards understanding magmatic processes involved in the generation of Large Igneous Provinces. I concentrate on the origin of variation in Cr in magmas and have developed a model in which high temperature melts intrude into and assimilate large amounts of upper continental crust.

Developing a therapeutic anti-dendritic cell antibody to prevent graft versus host disease

Host and donor dendritic cells (DC) stimulate alloreactive donor T lymphocytes, and initiate GVHD. We have shown that polyclonal antibody to the DC surface activation marker human CD83 (anti hCD83), which depletes activated DC, can prevent human DC and T cell induced lethal xenogeneic GVHD in SCID mice without impairing T cell mediated anti-leukaemic and anti-viral (CMV and influenza) immunity (J Exp Med 2009; 206: 387). Therefore, we made and tested a polyclonal anti mouse CD83 (RAM83) antibody in murine HSCT models and developed a human mAb against hCD83 as a potential new therapeutic immunosuppressive agent.

Process quality indicators targeting cognitive impairment to support quality of care for older people with cognitive impairment in emergency departments

Objectives The objective of this study was to develop process quality indicators (PQIs) to support the improvement of care services for older people with cognitive impairment in emergency departments (ED). Methods A structured research approach was taken for the development of PQIs for the care of older people with cognitive impairment in EDs, including combining available evidence with expert opinion (phase 1), a field study (phase 2), and formal voting (phase 3). A systematic review of the literature identified ED processes targeting the specific care needs of older people with cognitive impairment. Existing relevant PQIs were also included. By integrating the scientific evidence and clinical expertise, new PQIs were drafted and, along with the existing PQIs, extensively discussed by an advisory panel. These indicators were field tested in eight hospitals using a cohort of older persons aged 70 years and older. After analysis of the field study data (indicator prevalence, variability across sites), in a second meeting, the advisory panel further defined the PQIs. The advisory panel formally voted for selection of those PQIs that were most appropriate for care evaluation. Results In addition to seven previously published PQIs relevant to the care of older persons, 15 new indicators were created. These 22 PQIs were then field tested. PQIs designed specifically for the older ED population with cognitive impairment were only scored for patients with identified cognitive impairment. Following formal voting, a total of 11 PQIs were included in the set. These PQIs targeted cognitive screening, delirium screening, delirium risk assessment, evaluation of acute change in mental status, delirium etiology, proxy notification, collateral history, involvement of a nominated support person, pain assessment, postdischarge follow-up, and ED length of stay. Conclusions This article presents a set of PQIs for the evaluation of the care for older people with cognitive impairment in EDs. The variation in indicator triggering across different ED sites suggests that there are opportunities for quality improvement in care for this vulnerable group. Applied PQIs will identify an emergency services' implementation of care strategies for cognitively impaired older ED patients. Awareness of the PQI triggers at an ED level enables implementation of targeted interventions to improve any suboptimal processes of care. Further validation and utility of the indicators in a wider population is now indicated.

Structural quality indicators to support quality of care for older people with cognitive impairment in emergency departments

Objectives The purpose of this study was to identify the structural quality of care domains and to establish a set of structural quality indicators (SQIs) for the assessment of care of older people with cognitive impairment in emergency departments (EDs). Methods A structured approach to SQI development was undertaken including: 1) a comprehensive search of peer-reviewed and gray literature focusing on identification of evidence-based interventions targeting structure of care of older patients with cognitive impairment and existing SQIs; 2) a consultative process engaging experts in the care of older people and epidemiologic methods (i.e., advisory panel) leading to development of a draft set of SQIs; 3) field testing of drafted SQIs in eight EDs, leading to refinement of the SQI set, and; 4) an independent voting process among the panelists for SQI inclusion in a final set, using preestablished inclusion and exclusion criteria. Results At the conclusion of the process, five SQIs targeting the management of older ED patients with cognitive impairment were developed: 1) the ED has a policy outlining the management of older people with cognitive impairment during the ED episode of care; 2) the ED has a policy outlining issues relevant to carers of older people with cognitive impairment, encompassing the need to include the (family) carer in the ED episode of care; 3) the ED has a policy outlining the assessment and management of behavioral symptoms, with specific reference to older people with cognitive impairment; 4) the ED has a policy outlining delirium prevention strategies, including the assessment of patients' delirium risk factors, and; 5) the ED has a policy outlining pain assessment and management for older people with cognitive impairment. Conclusions This article presents a set of SQIs for the evaluation of performance in caring for older people with cognitive impairment in EDs.

Proactive behavior-based safety management for construction safety improvement

Construction is one of the most hazardous industries due to its dynamic, temporary, and decentralized nature. The Hong Kong Commissioner for Labor identifies worker behavior as the root cause of construction accidents. Behavior-based safety (BBS) is one effective approach in managing employee safety issues. However, there is little research on the application of BBS in the construction industry. This research proposes an extension of the BBS approach, proactive behavior-based safety (PBBS), to improve construction safety. PBBS integrates the theory of BBS with the technology of Proactive Construction Management System (PCMS). The innovations of PBBS are: (1) automatically monitoring location-based behaviors; (2)quantitatively measuring safety performance; (3) investigating potential causes of unsafe behaviors; and (4) improving the efficiency of safety management. A pilot study of a Hong Kong construction site practicing PBBS was conducted. The experiment results showed that PBBS performed well on construction accident prevention and the Safety Index (SI) of the two project teams, with increased improvements by 36.07% and 44.70% respectively. It is concluded that PBBS is effective and adaptable to construction industry.

Gearing up academics for collaborative Building Information Modelling (BIM) education

Building information modelling (BIM) radically changes the practices in architecture, engineering and construction (AEC) and creates new job opportunities. Many governments, such as the United Kingdom, have made BIM a mandatory requirement. This substantially drives the demand for a BIM-literate workforce. Universities are facing the challenge to incorporate BIM into their curricula and produce “BIM ready” graduates to meet the needs of the industry. Like other universities, Queensland University of Technology (QUT) is at the heart of this change and aspires to develop collaborative BIM education across AEC. Previous BIM education studies identify that inadequate BIM awareness of AEC academics is one of the challenges for developing a BIM curriculum and there is a dearth in the learning and teaching support for academics on BIM education. Equipping the AEC academics for a more BIM focused curriculum is all the while more important. This paper aims to leverage knowledge drawn from a Learning & Teaching project currently undertaken at QUT. Its specific objectives are to: 1) review the existing learning and teaching initiatives on BIM education; and 2) briefly describe the learning and teaching activities on collaborative BIM education at QUT. Significance of the paper lies on revealing the importance of building up the capacity of AEC academics for collaborative BIM education. The paper contributes to sparking the interests in better equipping AEC academics to understand what curriculum changes would assist in BIM uptake within the relevant courses to provide context for changes in units; and how the use of BIM can improve the understanding by students of the large amounts of professional knowledge they need to function effectively as graduates.