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Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
Neuregulin1 (Nrg1) is a candidate gene linked to schizophrenia. Cleavage of Nrg1 full-length (Nrg1-FL) precursor protein by BACE1 mediates activation of erbB receptors and triggers a cascade of downstream signalling events that lead to activation of GABA, NMDA, and nicotinic receptors. Studies with BACE1 knock out mouse models have demonstrated impaired Nrg1-/ErbB signalling leads to SZ-like phenotypes that can be rescued by antipsychotics.
We analysed frontal cortex brain tissue of schizophrenia (SZ) and healthy control (HC) subjects for expression of BACE1, Nrg1-FL and Nrg1 cleaved fragment.
To explore the possible mis-cleavage of Nrg1 by BACE1 in SZ as this may disrupt some neuronal circuits in the brain and trigger schizophrenia.
Samples from Brodmann area 6 region (40 SZ and 20 HC) were homogenized with TRIzol and proteins were analysed by western blotting. Also samples were analysed for RNA integrity and 18 SZ and 20 HC with high RIN were selected for qRT-PCR study.
About 50% decrease in Nrg1 C-terminal fragment (CTF) was observed in the SZ group compared to the HC group (p < 0.001). A strong correlation between Nrg-FL and BACE1 was observed (r = 0.82, P < 0.001). Results of qRT-PCR showed a significant increase in the expression of BACE1-432 splice variant in SZ compared to HC (P = 0.005). A strong inverse correlation was found between BACE1 activity and 432/501 BACE1 splice variants expression.
Our results suggest that altered expression of BACE1 and decreased cleavage of Nrg1 are associated with SZ.
Implementation of a novel experimental approach using a bright source of narrowband x-ray emission has enabled the production of a photoionized argon plasma of relevance to astrophysical modelling codes such as Cloudy. We present results showing that the photoionization parameter ζ = 4πF/ne generated using the VULCAN laser was ≈ 50 erg cm s−1, higher than those obtained previously with more powerful facilities. Comparison of our argon emission-line spectra in the 4.15 - 4.25 Å range at varying initial gas pressures with predictions from the Cloudy code and a simple time-dependent code are also presented. Finally we briefly discuss how this proof-of-principle experiment may be scaled to larger facilities such as ORION to produce the closest laboratory analogue to a photoionized plasma.
The pore structure of vapour deposited ASW is poorly understood, despite its importance to fundamental processes such as grain chemistry, cooling of star forming regions, and planet formation. We studied structural changes of vapour deposited D2O on intra-molecular to 30 nm length scales at temperatures ranging from 18 to 180 K and observed enhanced mobility from 100 to 150 K. An Arrhenius type model describes the loss of surface area and porosity with a common set of kinetic parameters. The low activation energy (428 K) is commensurate with van der Waals forces between nm-scale substructures in the ice. Our findings imply that water porosity will always change with time, even at low temperatures.
Salmonella enterica serovar Wangata (S. Wangata) is an important cause of endemic salmonellosis in Australia, with human infections occurring from undefined sources. This investigation sought to examine possible environmental and zoonotic sources for human infections with S. Wangata in north-eastern New South Wales (NSW), Australia. The investigation adopted a One Health approach and was comprised of three complimentary components: a case–control study examining human risk factors; environmental and animal sampling; and genomic analysis of human, animal and environmental isolates. Forty-eight human S. Wangata cases were interviewed during a 6-month period from November 2016 to April 2017, together with 55 Salmonella Typhimurium (S. Typhimurium) controls and 130 neighbourhood controls. Indirect contact with bats/flying foxes (S. Typhimurium controls (adjusted odds ratio (aOR) 2.63, 95% confidence interval (CI) 1.06–6.48)) (neighbourhood controls (aOR 8.33, 95% CI 2.58–26.83)), wild frogs (aOR 3.65, 95% CI 1.32–10.07) and wild birds (aOR 6.93, 95% CI 2.29–21.00) were statistically associated with illness in multivariable analyses. S. Wangata was detected in dog faeces, wildlife scats and a compost specimen collected from the outdoor environments of cases’ residences. In addition, S. Wangata was detected in the faeces of wild birds and sea turtles in the investigation area. Genomic analysis revealed that S. Wangata isolates were relatively clonal. Our findings suggest that S. Wangata is present in the environment and may have a reservoir in wildlife populations in north-eastern NSW. Further investigation is required to better understand the occurrence of Salmonella in wildlife groups and to identify possible transmission pathways for human infections.
Defined as the co-occurrence of more than two chronic conditions, multi-morbidity has been described as a significant health care problem: a trend linked to a rise in non-communicable disease and an ageing population. Evidence on the experiences of living with multi-morbidity in middle-income countries (MICs) is limited. In high-income countries (HICs), multi-morbidity has a complex impact on health outcomes, including functional status, disability and quality of life, complexity of health care and burden of treatment. Previous evidence also shows that multi-morbidity is consistently higher amongst women. This study aimed to explore the perceptions and experiences of women living with multi-morbidity in the Greater Accra Region, Ghana: to understand the complexity of their health needs due to multi-morbidity, and to document how the health system has responded. Guided by the Cumulative Complexity Model, and using stratified purposive sampling, 20 in-depth interviews were conducted between May and September 2015 across three polyclinics in the Greater Accra Region. The data were analysed using the six phases of Thematic Analysis. Overall four themes emerged: 1) the influences on patients’ health experience; 2) seeking care and the responsiveness of the health care system; 3) how patients manage health care demands; and 4) outcomes due to health. Spirituality and the stigmatization caused by specific conditions, such as HIV, impacted their overall health experience. Women depended on the care and treatment provided through the health care system despite inconsistent coverage and a lack of choice thereof, although their experiences varied by chronic condition. Women depended on their family and community to offset the financial burden of treatment costs, which was exacerbated by having many conditions. The implications are that integrated health and social support, such as streamlining procedures and professional training on managing complexity, would benefit and reduce the burden of multi-morbidity experienced by women with multi-morbidity in Ghana.
To determine whether the use of enhanced isolation precautions (droplet and contact precautions) for inpatients with respiratory tract viral infections is associated with a reduction in rate of nosocomial viral respiratory infections.
Quasi-experimental study with the rate of nosocomial respiratory virus infection as the primary dependent variable and rate of nosocomial Clostridium difficile infection as a nonequivalent dependent variable comparator.
Cohen Children’s Medical Center of NY, a tertiary-care children’s hospital attached to a large general hospital.
During years 1 and 2 (July 2012 through June 2014), the Centers for Disease Control and Prevention/Healthcare Infection Control Practices Advisory Committee’s recommended isolation precautions for inpatients with selected respiratory virus infections were in effect. Enhanced isolation precautions were in effect during years 3 and 4 (July, 2014 through June, 2016), except for influenza, for which enhanced precautions were in effect during year 4 only.
During the period of enhanced isolation precautions, the rate of nosocomial respiratory virus infections with any of 4 virus categories decreased 39% from 0.827 per 1,000 hospital days prior to enhanced precautions to 0.508 per 1,000 hospital days (P<.0013). Excluding rhinovirus/enterovirus infections, the rates decreased 58% from 0.317 per 1,000 hospital days to 0.134 per 1,000 hospital days during enhanced precautions (P<.0014). During these periods, no significant change was detected in the rate of nosocomial C. difficile infection.
Enhanced isolation precautions for inpatients with respiratory virus infections were associated with a reduction in the rate of nosocomial respiratory virus infections.
Excommunication resulted in complete separation from the Christian community. This basic definition can be accepted without difficulty. To go further, however, is problematic. Excommunication's precise implications were far from clear. An excommunicate was to be shunned by all other Christians; he or she could not be buried in ecclesiastical ground and was unable to sue in court. Yet excommunication was also a spiritual sanction. A frequently cited canon from Gratian's Decretum defined anathema as ‘damnation of eternal death’. Nevertheless, in 1245, at the first Council of Lyons, Pope Innocent IV emphatically asserted, ‘Excommunication is medicine not death, discipline not annihilation.’ This decree, known as ‘Cum medicinalis’, added to an already significant body of canon law intended to ensure that clerics used excommunication justly, and sparingly. In the same period, theologians had reached a consensus that excommunication was not a curse and did not send a person to hell. Yet excommunication continued to be ‘burdened with great ambivalence’, as Elisabeth Vodola has observed. Despite the definition in ‘Cum medicinalis’ and the assurances of theologians, it was not uncommon throughout the Middle Ages for both churchmen and laymen to believe that excommunication resulted in ‘misfortune in this world and damnation in the next’.
This observation is hardly new. Martin Luther complained about the problem as early as 1518. The most full study of this tension is Alexander Murray's 1991 John Coffin Memorial Lecture, in which he explores the complexity of the issues at stake. Vodola and R.H. Helmholz have likewise carefully noted that excommunication remained linked to cursing long after the thirteenth century. Nevertheless, the years surrounding 1200 have been seen as a turning point. Thus for Vodola, by the early thirteenth century, ‘it was evident … that major excommunication concerned only the punishment that detained a soul in purgatory, not the guilt that consigned it to hell’. Helmholz has described a competition during the twelfth century between two conceptions of excommunication: judicial sanction versus powerful curse. He argues that the former had won a (qualified) victory by the end of the century. That the first writs ordering recalcitrant excommunicates to be detained by the secular arm date from the beginning of the thirteenth century further indicates a watershed in the development of excommunication around this time.
Terrestrial gastropods are problematical for radiocarbon (14C) measurement because they tend to incorporate carbon from ancient sources as a result of their dietary behavior. The 14C ecology of the pulmonate land snail, Helix melanostoma in Cyrenaica, northeastern Libya, was investigated as part of a wider study on the potential of using terrestrial mollusk shell for 14C dating of archaeological deposits. H. melanostoma was selected out of the species available in the region as it has the most predictable 14C ecology and also had a ubiquitous presence within the local archaeology. The ecological observations indicate that H. melanostoma has a very homogenous 14C ecology with consistent variations in F14C across sample sites controlled by availability of dietary vegetation. The majority of dated specimens from non-urbanized sample locations have only a small old-carbon effect, weighted mean of 476±48 14C yr, with between ~1% and 9% of dietary F14C from non-organic carbonate sources. Observed instabilities in the 14C ecology can all be attributed to the results of intense human activity not present before the Roman Period. Therefore, H. melanostoma and species with similar ecological behavior are suitable for 14C dating of archaeological and geological deposits with the use of a suitable offset.
Background: Traditional neurosurgical techniques and/or stereotactic radiotherapy, although effective for solid tumors, can be associated with high morbidity and be relatively ineffective for long-term control of cystic sellar/parasellar tumors. The rationale of our study was to examine the efficacy and safety of stereotactic intracavitary instillation of 90yttrium colloid for the primary treatment of cystic tumors. Methods: As part of a Health Canada approved clinical trial, we have enrolled nine patients (6 females, 3 males; mean age 64, range 43 to 83 years) for treatment of symptomatic and/or enlarging cysts. Ten cystic sellar/parasellar lesions underwent right frontal stereotactic insertion of 90yttrium colloid to deliver a radiation dose of 200 Gy to the cyst wall. Results: Compared with pre-treatment cyst volumes (mean 4.6 cc; range 0.8-16.1 cc), the cysts decreased in size at 3 months (2.6 cc; 0.2-10 cc) with further shrinkage (n=5) at 9 months (1 cc; 0.1-2.7 cc). Of 9 patients with pre-operation visual field defects, 6 showed improvement. The single complication was a delayed (1 month) incomplete CNIII palsy. Conclusions: Our early experience indicates that 90yttrium colloid delivered to a cystic craniopharyngioma provides an efficacious alternative to open surgery for primary treatment of these cystic lesions.
The Tasmanian Cenozoic macrofossil record is relatively rich, and changes that have occurred in the vegetation of the region are becoming increasingly well understood. The record is essentially one of rainforest elements, especially in the Paleogene, but taxa that are now common in sclerophyllous heathlands and woodlands are increasingly prevalent in Quaternary sediments.
Extant Tasmanian rainforest is renowned for its beauty, and botanists have long recognised its marked taxonomic and structural similarity to other southern hemisphere ‘cool temperate’ forests of New Zealand and Chile. These are generally dominated by Nothofagus trees, their boughs laden with lichens and verdant shrouds of bryophytes. Other links are often made by phytogeographers to similar forests in high altitude regions of northern New South Wales and the much more species-rich vegetation of the generally montane regions of New Guinea and New Caledonia where Nothofagus also grows. A striking aspect of these forests is the presence of a variety of conifers, principally Podocarpaceae, but also Cupressaceae and Araucariaceae. In Tasmania the Araucariaceae are extinct, but the region is unique in the southern hemisphere in having a genus of Taxodiaceae, Athrotaxis. Athrotaxis spp. are often associated with Australia's only winter deciduous plant, Nothofagus gunnii, in montane regions of the island. The macrofossil record shows conclusively that the current diversity of Tasmania's woody rainforest flora is very much lower than at any other time during the Cenozoic. It confirms that there are strong floristic links to regions as widespread as eastern and southwestern mainland Australia, southern South America, New Zealand and New Guinea. In fact, Tasmanian Paleogene floras contain a wealth of taxa that are closely related to plants now confined to these regions.
Apart from the relatively large tracts of rainforest in Tasmania, closed forest lacking eucalypts is now confined to small patches along the east coast of Australia. In contrast to mainland Australia, Tasmania is relatively mountainous and has a well-developed woody alpine vegetation, dominated by shrubs of the Asteraceae, Epacridaceae, Myrtaceae and Proteaceae.
This study examines the interplay between individual and social–developmental factors in the development of positive functioning, substance use problems, and mental health problems. This interplay is nested within positive and negative developmental cascades that span childhood, adolescence, the transition to adulthood, and adulthood. Data are drawn from the Seattle Social Development Project, a gender-balanced, ethnically diverse community sample of 808 participants interviewed 12 times from ages 10 to 33. Path modeling showed short- and long-term cascading effects of positive social environments, family history of depression, and substance-using social environments throughout development. Positive family social environments set a template for future partner social environment interaction and had positive influences on proximal individual functioning, both in the next developmental period and long term. Family history of depression adversely affected mental health functioning throughout adulthood. Family substance use began a cascade of substance-specific social environments across development, which was the pathway through which increasing severity of substance use problems flowed. The model also indicated that adolescent, but not adult, individual functioning influenced selection into positive social environments, and significant cross-domain effects were found in which substance-using social environments affected subsequent mental health.
Studies have demonstrated that the effects of two well-known predictors of adolescent substance use, family monitoring and antisocial peers, are not static but change over the course of adolescence. Moreover, these effects may differ for different groups of youth. The current study uses time-varying effect modeling to examine the changes in the association between family monitoring and antisocial peers and marijuana use from ages 11 to 19, and to compare these associations by gender and levels of behavioral disinhibition. Data are drawn from the Raising Healthy Children study, a longitudinal panel of 1,040 youth. The strength of association between family monitoring and antisocial peers and marijuana use was mostly steady over adolescence, and was greater for girls than for boys. Differences in the strength of the association were also evident by levels of behavioral disinhibition: youth with lower levels of disinhibition were more susceptible to the influence of parents and peers. Stronger influence of family monitoring on girls and less disinhibited youth was most evident in middle adolescence, whereas the stronger effect of antisocial peers was significant during middle and late adolescence. Implications for the timing and targeting of marijuana preventive interventions are discussed.
Methods were developed and tested for mapping the distribution of Scotch broom, an invasive shrub species expanding its range and disrupting native species and habitats in several parts of the world. During spring, the Scotch broom produces yellow flowers. Landsat imagery during the flower bloom period and during summer was acquired for several years for a study area on Vancouver Island, British Columbia, Canada. Ground-based reflectance measurements plus statistical separability tests were conducted to determine the effectiveness for identifying Scotch broom with Landsat spectral bands, band ratios, vegetation indices, and combinations of bloom and nonbloom imagery. Maximum likelihood classifications of three Scotch broom density classes (dense, ≥ 75% cover; moderate, 25 to 75%; low, 10 to 25%) and other land covers were run with various image and band sets and tested against independent reference sites. Accuracies of classifications using the better band combinations for moderate and dense Scotch broom patches combined were on the order of 80%, with unreliable results for sites of low Scotch broom density. Scotch broom patches less than 0.5 ha were often missed. Some commission error occurred (areas erroneously classified as Scotch broom). Suggested improvements are the use of time series of classifications over multiple years, incorporating knowledge of Scotch broom spread mechanisms or temperature and elevation limitations, and use of higher resolution satellites if the expense warrants it. Despite some limitations, a satellite-based remote sensing approach may be useful for aspects of Scotch broom management.
The aim of this study was to contribute to the better understanding of the relative epidemiological importance of different modes of infection with respect to horizontal transmission of Toxoplasma gondii in endemic settings. We investigated the prevalence of salivary IgA against a sporozoite-specific embryogenesis-related protein (TgERP) in a highly endemic area for toxoplasmosis in Brazil in order to pinpoint parasite transmission via oocysts. Prevalence calculated by salivary IgA specific to TgERP was compared to the prevalence calculated by serum IgG against both TgERP and tachyzoites (in conventional serological tests). Prevalence calculated by different serological and salivary parameters varied in the studied age groups. However, for the 15–21 years age group, values for T. gondii prevalence estimated by conventional serological tests and by anti-TgERP salivary IgA were similar; i.e. 68·7% and 66·6% or 66·7%, respectively, using two different cut-off parameters for salivary IgA anti-TgERP. Furthermore, salivary IgA anti-TgERP for this age group presented the highest specificity (93·33%), sensitivity (93·94%), and likelihood (14·09) compared to all the other age groups. These data demonstrate the importance of age for salivary IgA investigation against TgERP to estimate the mode of T. gondii transmission in endemic settings.