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Generation of cardio-protective antibodies after pneumococcal polysaccharide vaccine: Early results from a randomised controlled trial
No full textBackground and aims: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. Methods: A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). Results: Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. Conclusions: PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events
Job creation and destruction in Taiwan
No full textThis thesis explores the behaviour of job flows in Taiwan. The investigation of the behaviour of job creation and destruction has improved our understanding of the dynamics of the Taiwanese labour market and also has important implications in terms of economic research and policymaking.
Chapter 2 discusses the basic features of the overall post-war Taiwanese economy. We find that large flows of workers enter and exit the employment pool. The large worker flows offer an interesting insight about the job flow dynamics. Based on the measures proposed in Chapter 3, Chapter 4 carefully examines the so-called small business job creation hypothesis. We find that small business can be viewed as the engine of job creation. However, small business is not the source of sustained increases in employment. Chapter 5 documents the basic features of job creation and destruction. We find that job creation is more volatile than job destruction in the manufacturing and service sectors, but reveals the opposite pattern in the construction sector. Based on the methodologies outlined in Chapter 6, Chapter 7 investigates the regime switching and asymmetric behaviour of job creation and destruction. We find that the interest rate can help to explain the asymmetric behaviour of job creation and destruction rates in all sectors. Furthermore, we find an interesting feature that a lower interest rate stimulated beneficial regime shifts in job flows. Chapter 8 explores the similarities and differences of regional business cycles by reference to the employment growth rate as well as job creation and destruction rates. We find that the regime switching behaviour of employment growth was similar across the North, Central and South regions. However, behaviour in the East Region was dramatically different. Furthermore, the regime switching behaviour of the common regional business cycle (specified in terms of employment growth) is consistent with the business cycle indicator proposed by Council for Economic Planning and Development (CEPD)
Pan-cancer analysis of whole genomes
No full textCancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18
ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration.
No full textStem cell approaches have become an attractive therapeutic option for intervertebral disc degeneration (IVDD). Nucleus pulposus mesenchymal stem cells (NP-MSCs) participate in the regeneration and homeostasis of the intervertebral disc (IVD), but the molecular mechanisms governing these processes remain to be elucidated. Acid-sensing ion channels (ASICs) which act as key receptors for extracellular protons in central and peripheral neurons, have been implicated in IVDD where degeneration is associated with reduced microenvironmental pH. Here we show that ASIC1 and ASIC3, but not ASIC2 and ASIC4 are upregulated in human IVDs according to the degree of clinical degeneration. Subjecting IVD-derived NP-MSCs to pH 6.6 culture conditions to mimic pathological IVD changes resulted in decreased cell proliferation that was associated with cell cycle arrest and induction of senescence. Key molecular changes observed were increased expression of p53, p21, p27, p16 and Rb1. Instructively, premature senescence in NP-MSCs could be largely alleviated using ASIC inhibitors, suggesting both ASIC1 and ASIC3 act decisively upstream to activate senescence programming pathways including p53-p21/p27 and p16-Rb1 signaling. These results highlight the potential of ASIC inhibitors as a therapeutic approach for IVDD and broadly define an in vitro system that can be used to evaluate other IVDD therapies
Dysfunction in macula, retinal pigment epithelium and post retinal pathway in acute organophosphorus poisoning
No full textContext: Organophosphorus (OP) insecticide poisoning is a significant health problem in South Asian countries. Although cholinergic receptors are present at the junction between photoreceptors and the retinal pigment epithelium (RPE), human studies of the effects of OP poisoning on the visual pathways are very few. This study aims to demonstrate the pattern of changes in retina and post retinal pathways in patients with acute OP poisoning using visual electrophysiological tests. Methods: This is an observational, cross-sectional study conducted at the Neurophysiology Unit, Teaching Hospital, Peradeniya, Sri Lanka. We tested 16 patients recovered from cholinergic phase, at least 24 h after deatropinization and within 8 weeks of OP ingestion. We assessed the functional integrity of the photoreceptors and ganglion cells of the macula by pattern electroretinography (PERG); RPE by electro-oculography (EOG); and post retinal pathways by pattern reversal visual evoked potentials (PR-VEP). Latencies and amplitudes of PR-VEP and PERG, light peak (LP), dark trough (DT) and Arden ratio of EOG were determined in patients and compared with 16 controls using the Mann–Whitney U test. Results: Of the 16 OP-poisoned patients (median age of 37 ± IQR 20 years), six (37.5%) had reduced Arden ratio with reference to the International Society of Clinical Electrophysiology of Vision cut-off value of 1.7. The median Arden ratio in patients (1.69 ± IQR 0.36) was significantly lower compared to controls (1.90 ± IQR 0.4). The median latencies and amplitudes of PR-VEP or PERG were not significantly different between patients and controls. However, three patients had prolonged P100 latencies in PR-VEP and one had prolonged P50 latency in PERG. Conclusions: Acute OP poisoning seems to affect the functions of the RPE and the visual electrophysiological changes outlast the cholinergic phase. Limited evidence suggests that photoreceptors of the macula region and post retinal pathway might be affected in some patients
A novel quality assurance procedure for trajectory log validation using phantom-less real-time latency corrected EPID images
No full textThe use of trajectory log files for routine patient quality assurance is gaining acceptance. Such use requires the validation of the trajectory log itself. However, the accurate localization of a multileaf collimator (MLC) leaf while it is in motion remains a challenging task. We propose an efficient phantom-less technique using the EPID to verify the dynamic MLC positions with high accuracy. Measurements were made on four Varian TrueBeams equipped with M120 MLCs. Two machines were equipped with the S1000 EPID; two were equipped with the S1200 EPID. All EPIDs were geometrically corrected prior to measurements. Dosimetry mode EPID measurements were captured by a frame grabber card directly linked to the linac. All leaf position measurements were corrected both temporally and geometrically. The readout latency of each panel, as a function of pixel row, was determined using a 40 x 1.0 cm2 sliding window (SW) field moving at 2.5 cm/s orthogonal to the row readout direction. The latency of each panel type was determined by averaging the results of two panels of the same type. Geometric correction was achieved by computing leaf positions with respect to the projected isocenter position as a function of gantry angle. This was determined by averaging the central axis position of fields at two collimator positions of 90° and 270°. The radiological to physical leaf end position was determined by comparison of the measured gap with that determined using a feeler gauge. The radiological to physical leaf position difference was found to be 0.1 mm. With geometric and latency correction, the proposed method was found to be improve the ability to detect dynamic MLC positions from 1.0 to 0.2 mm for all leaves. Latency and panel residual geometric error correction improve EPID-based MLC position measurement. These improvements provide for the first time a trajectory log QA procedure
Changes in the incidence of assault after restrictions on late-night alcohol sales in New Zealand: evaluation of a natural experiment using hospitalization and police data
No full textAims: To estimate the effect of national restrictions on late‐night availability of alcohol on alcohol‐related assault at a population level as indicated by (1) change in hospitalizations for weekend assaults and (2) change in the proportion of assaults documented by police that occur at night. Design Evaluation of a natural experiment, involving: (1) pre–post comparisons of age‐specific incidence rates, adjusted for seasonality and background trend using Poisson regression;and (2) interrupted time–series analyses, using seasonal auto regressive integrated moving average (SARIMA) models of national data with no control site. Setting: New Zealand. Participants: (1) Inpatients discharged from NZ hospitals following assault during the weekend (Friday–Sunday) from 2004 to 2016 (n= 14996) and (2) cases of assault recorded by NZ Police from 2012 to 2018. Intervention: introduction of national maximum trading hours for all on‐licence (8 a.m.–4 a.m.) and off‐licence premises (7 a.m.–11 p.m.), abolishing existing 24‐hour licences, on 18 December 2013. Measurements: (1) Age‐specific incidence of hospitalization for assault on Friday, Saturday or Sunday from the national hospital discharge data set, excluding short‐stay emergency department admissions and (2) proportion of weekly police‐documented assaults occurring between 9 p.m. and 5.59 a.m., from NZ Police Demand and Activity data set. Findings: Following the restrictions, weekend hospitalized assaults declined by 11% [incidence rate ratio(IRR) = 0.89; 95% confidence interval (CI) = 0.84, 0.94], with the greatest reduction among 15–29‐year‐olds(IRR = 0.82; 95% CI = 0.76, 0.89). There was an absolute reduction (step change) of 1.8% (95% CI = 0.2, 3.5%) in the proportion of police‐documented assaults occurring at night, equivalent to 9.70 (95% CI = 0.10, 19.30) fewer night‐time assaults per week, out of 207.4. Conclusions: The 2013 implementation of national maximum trading hours for alcohol in NZ was followed by reductions in two complementary indicators of alcohol‐related assault, consistent with beneficial effects of modest nation‐wide restrictions on the late‐night availability of alcohol
Scheduling of maintenance windows in a mining supply chain rail network
No full textRail infrastructure forms a critical part of the mining supply chain in Australia due to the high weight to volume ratio of the product and the long distances between the mines and the ports. Across Australia, rail infrastructure has been steadily expanding to account for the growth in export volumes and the movement of mining operations further inland, and so the efficient and effective management of this critical infrastructure is vitally important. Maintenance plays a crucial role in this management as it ensures that the infrastructure assets are in a condition that allows safe, reliable, and efficient transport. In this paper we consider the annual planning of maintenance for Australia’s largest coal rail network, the Central Queensland Coal Network (CQCN), that is owned, operated, and managed, by Aurizon Holdings Pty Ltd. The current planning approach at Aurizon uses the concept of a maintenance access window (MAW) which provides a train-free time window across geographically contiguous track locations that define a maintenance zone. These train-free time windows facilitate the scheduling of specific maintenance tasks at specific track locations within zones closer to day of operation and forms the basis for a planning framework. A MIP model is introduced which facilitates the planning of different maintenance resources across this network to schedule MAWs. The model takes into account maintenance requirement forecasts as well as the availability of resources. Candidate solutions are compared using a proxy for network throughput capacity. Due to the long computation times required to solve the MIP model at the annual planning horizon a matheuristic is developed and two variants are tested. On average 80% less computational time is required to find a good solution (average gap of 5%) using the matheuristic compared to solving the MIP model directly (average gap of 1.5%). The MIP model and associated matheuristic provides a suitable framework for semi-automated maintenance planning and is being integrated into the current suite of decision support tools used by Aurizon
Erythrocyte microRNAs show biomarker potential and implicate multiple sclerosis susceptibility genes
No full textBackground: Multiple sclerosis is a demyelinating autoimmune disease, for which there is no blood-borne biomarker. Erythrocytes may provide a source of such biomarkers as they contain microRNAs. MicroRNAs regulate protein translation through complementary binding to messenger RNA. As erythrocytes are transcriptionally inactive, their microRNA profiles may be less susceptible to variation. The aim of this study was to assess the biomarker potential of erythrocyte microRNAs for multiple sclerosis and assess the potential contribution of erythrocyte-derived extracellular vesicle microRNAs to pathology. Methods: Erythrocytes were isolated from whole blood by density gradient centrifugation. Erythrocyte microRNAs of a discovery cohort (23 multiple sclerosis patients and 22 healthy controls) were sequenced. Increased expression of miR-183 cluster microRNAs (hsa-miR-96-5p, hsa-miR-182-5p and hsa-miR-183-5p) was validated in an independent cohort of 42 patients and 45 healthy and pathological (migraine) controls. Erythrocyte-derived extracellular vesicles were created ex vivo and their microRNAs were sequenced. Targets of microRNAs were predicted using miRDIP. Results: Hsa-miR-182-5p and hsa-miR-183-5p were able to discriminate relapsing multiple sclerosis patients from migraine patients and/or healthy controls with 89-94% accuracy and around 90% specificity. Hsa-miR-182-5p and hsa-miR-183-5p expression correlated with measures of physical disability and hsa-miR-96-5p expression correlated with measures of cognitive disability in multiple sclerosis. Erythrocytes were found to selectively package microRNAs into extracellular vesicles and 34 microRNAs were found to be differentially packaged between healthy controls and multiple sclerosis patients. Several gene targets of differentially expressed and packaged erythrocyte microRNAs overlapped with multiple sclerosis susceptibility genes. Gene enrichment analysis indicated involvement in nervous system development and histone H3-K27 demethylation. Conclusions: Erythrocyte miR-183 cluster members may be developed into specific multiple sclerosis biomarkers that could assist with diagnosis and disability monitoring. Erythrocyte and their extracellular microRNAs were shown to target multiple sclerosis susceptibility genes and may be contributing to the pathophysiology via previously identified routes
Caregivers' Falls Concern for Older Persons in the Singapore Community
No full textThis paper discusses the prevalence of caregivers' concern, its impact on fall prevention strategies, falls risk awareness among older persons, clinical points, and study potential. Older persons suffering from fall-related psychological concerns such as fear of falling has been well established in previous research, however little is known about caregivers' falls concern in its relationship with the risk of older persons falling. In Singapore, families are regarded as the fundamental support system for older people. The potential influence of caregivers' concern on the outcome of fall prevention strategies and falls risk awareness of older persons is expected given their significant involvement in the older persons' care. However, it is difficult to accurately appreciate the impact of caregivers' falls concern on the risk of falls among older persons in the local community given the Singaporean cultural differences and the dearth of Singaporean research on caregiver's concern. It is promulgated in this paper that further research should address the impact of caregivers' falls concern on fall-related issues associated with caring for an older person at risk of falling