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Contains fulltext : 293209.pdf (Publisher’s version ) (Open Access), A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

Contains fulltext : 208125.pdf (publisher's version ) (Open Access), Objective: To investigate the brain-derived neurotrophic factor (BDNF) and cognitive response to a short bout of high-intensity aerobic exercise in older adults with mild cognitive impairment (MCI). Methods: Participants were randomised to one of two testing schedules, completing either a standardised exercise test (group A) or a resting control condition (group B). Blood sampling and cognitive measures (visuospatial learning and memory, sustained attention and executive function) were collected at baseline (T1) and postintervention (T2). An additional measurement of study outcomes was collected after exercise (T3) in group B only. Results: 64 participants (female 53.2%, mean age 70.5+/-6.3 years) with MCI were recruited. From T1 to T2, serum BDNF (sBDNF) concentration increased in group A (n=35) (median (Md) 4564.61+/-IQR 5737.23 pg/mL to Md 5173.27+/-5997.54 pg/mL) and decreased in group B (Md 4593.74+/-9558.29 pg/mL to Md 3974.66+/-3668.22 pg/mL) (between-group difference p=0.024, effect size r=0.3). The control group made fewer errors on the sustained attention task compared with the exercise group (p=0.025). Measures of visuospatial learning and memory or executive function did not change significantly between groups. Conclusion: This study is the first to show that a short bout of high-intensity aerobic exercise increases peripheral sBDNF in a population with MCI. However, acute exercise did not improve cognitive performance.

Background and objective: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common presentation to emergency departments (ED) but data regarding its epidemiology and outcomes are scarce. We describe the epidemiology, clinical features, treatment and outcome of patients treated for AECOPD in ED. Method(s): This was a planned sub-study of patients with an ED diagnosis of AECOPD identified in the Asia, Australia and New Zealand Dyspnoea in Emergency Departments (AANZDEM) study. The AANZDEM was a prospective, interrupted time series cohort study conducted in 46 ED in Australia, New Zealand, Singapore, Hong Kong and Malaysia over three 72-h periods in May, August and October 2014. Primary outcomes were patient epidemiology, clinical features, treatment and outcomes (hospital length of stay (LOS) and mortality). Result(s): Forty-six ED participated. There were 415 patients with an ED primary diagnosis of AECOPD (13.6% of the overall cohort; 95% CI: 12.5-14.9%). Median age was 73 years, 60% males and 65% arrived by ambulance. Ninety-one percent had an existing COPD diagnosis. Eighty percent of patients received inhaled bronchodilators, 66% received systemic corticosteroids and 57% of those with pH < 7.30 were treated with non-invasive ventilation (NIV). Seventy-eight percent of patients were admitted to hospital, 7% to an intensive care unit. In-hospital mortality was 4% and median LOS was 4 days (95% CI: 2-7). Conclusion(s): Patients treated in ED for AECOPD commonly arrive by ambulance, have a high admission rate and significant in-hospital mortality. Compliance with evidence-based treatments in ED is suboptimal affording an opportunity to improve care and potentially outcomes.Copyright © 2018 Asian Pacific Society of Respirology

Objectives: The objective was to describe the epidemiology of dyspnea presenting to emergency departments (EDs) in the Asia-Pacific region, to understand how it is investigated and treated and its outcome. Method(s): Prospective interrupted time series cohort study conducted at three time points in EDs in Australia, New Zealand, Singapore, Hong Kong, and Malaysia of adult patients presenting to the ED with dyspnea as a main symptom. Data were collected over three 72-hour periods and included demographics, comorbidities, mode of arrival, usual medications, prehospital treatment, initial assessment, ED investigations, treatment in the ED, ED diagnosis, disposition from ED, in-hospital outcome, and final hospital diagnosis. The primary outcomes of interest are the epidemiology, investigation, treatment, and outcome of patients presenting to ED with dyspnea. Result(s): A total of 3,044 patients were studied. Patients with dyspnea made up 5.2% (3,105/60,059, 95% confidence interval [CI] = 5.0% to 5.4%) of ED presentations, 11.4% of ward admissions (1,956/17,184, 95% CI = 10.9% to 11.9%), and 19.9% of intensive care unit (ICU) admissions (104/523, 95% CI = 16.7% to 23.5%). The most common diagnoses were lower respiratory tract infection (20.2%), heart failure (14.9%), chronic obstructive pulmonary disease (13.6%), and asthma (12.7%). Hospital ward admission was required for 64% of patients (95% CI = 62% to 66%) with 3.3% (95% CI = 2.8% to 4.1%) requiring ICU admission. In-hospital mortality was 6% (95% CI = 5.0% to 7.2%). Conclusion(s): Dyspnea is a common symptom in ED patients contributing substantially to ED, hospital, and ICU workload. It is also associated with significant mortality. There are a wide variety of causes however chronic disease accounts for a large proportion.Copyright © 2016 by the Society for Academic Emergency Medicine

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.

Contains fulltext : 136954.pdf (publisher's version ) (Open Access), The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

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Objective: To compare the management of paediatric patients with mild or moderate asthma in paediatric-only emergency departments (POEDs) to treatment in a mixed adult-child emergency departments (mixed EDs). Method(s): Prospective, observational study conducted in 36 Australian emergency departments (EDs) for 2 weeks in 2001. Children aged 1-15 years with acute asthma classified as mild or moderate severity. Details of demography, severity assessment, and type of treatment facility, treatment and disposition were collected. Analysis used descriptive statistics, comparison of proportions by chi2, and multiple logistic regression. Result(s): Two-hundred and nine children were treated at POEDs and 257 at mixed EDs. The groups had similar severity. Spacers to deliver beta-agonists were used more frequently in POEDs (67.5% vs 24.2%; P < 0.01). Children treated at POEDs with a mild attack were more likely to be admitted (20.6% vs 9.5%; P < 0.02) and given salbutamol (82.8% vs 71.9%; P = 0.03). For children with moderate asthma, oral steroid prescription on hospital discharge was more common for those treated in a mixed ED (81.0% v 95.7%; P = 0.01). Ipratropium bromide (IB) was widely used at both types of ED but more commonly used in mixed EDs (41.7% vs 54.9%; P < 0.01). There were no differences in length-of-stay, representation rate within one month and oral steroid use for attack. Less than 2/3 of children with mild asthma attacks received steroid treatment in the ED. Conclusion(s): Treatment was similar between the two types of ED. IB was overused in mild asthma and oral steroids were underused in moderate asthma, by both ED types. Spacers were under-utilized in mixed EDs.

Barley hull plays an important role in malt and feed quality and processing. In this study we measured the variation in hull content along with other grain quality traits namely, kernel discolouration and degree of pre-harvest sprouting, in a single mapping population. There were significant (p < 0.05) genetic as well as environment effects. In addition, heritability was calculated for hull content to be 29% and 47% for two years' data. From the analysis, major QTL markers were identified in controlling the expression of hull content on chromosomes 2 (2H), and 6 (6H) with significant (P < 0.05) LOD scores of 5.4 and 3.46 respectively. Minor QTLs were identified on 1 (7H), 4 (4H), 5 (1H) and 7 (5H). The region at marker Bmac310 on 4(4H) could be associated with dormancy gene SD4. A number of the QTLs also coincided with regions for either kernel discolouration or preharvest sprouting resistance (dormancy). The results indicate that variation exists for hull content, which is influenced by both growing environment as well as genetically, although the genetic variance explained less than half of the total variance. Further, hull content also impacts on other grain quality attributes including dormancy, sprouting resistance and kernel appearance.