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This is a copy of the slides presented at the meeting but not formally
written up for the volume.
As in vivo cellular imaging becomes the necessary norm for understanding
cancer and other diseases, new non-toxic nanoprobes are going to be
required to replace the high quality cadmium based nanoprobes in use
today. We are developing less toxic probes based on two types of
luminescent ceramic nanoparticles: naturally occurring fluorescent (NOF)
mimics and Ln-based ceramic oxide materials. The NOF minerals of interest
and that have demonstrated initial luminosity of sufficient brightness
for use in cellular studies that include sphalerite, scheelite, manganoan
and perovskite nanoparticles. For Ln-based materials we have shown that
Ln-doped zincite will also luminesce enough to allow for quantification
in cellular activity. Once formed, these probes are functionalized such
that they can be delivered to desired cellular targets. Probe
derivatization has focused on surface capping with functionalized
poly(ethyleneglycol) molecules/lipids to yield water soluble NCs and
polyarginine-based transporters for transmembrane delivery. The probes
are being evaluated for their luminescent properties, as well as their
non-toxicity and ability to report on cell-signaling events with various
cell lines using multi-spectral, confocal microscopy, and other
techniques. Preliminary interdisciplinary studies have validated the
basic approaches for the synthesis of NOF nanoprobes and the bio-delivery
and imaging of nanoparticles. Work to optimize the design, delivery, and
imaging of these new nanoprobes is expected to achieve the NIH directed
goal of increasing in the sensitivity and specificity of molecular probes
for imaging. Details of the synthesis, functionalization and biological
imaging using these probes will be presented. This work partially
supported by the United States Department of Energy under contract number
DE-AC04-94AL85000. Sandia is a multi-program laboratory operated by
Sandia Corporation, a Lockheed-Martin Company, for the United States
Department of Energy and by the National Institutes of health through the
NIH Roadmap for Medical Research, Grant #1 R21 EB005365-01. Information
on this RFA (Innovation in Molecular Imaging Probes) can be found at http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-021.html.
To enhance enrollment into randomized clinical trials (RCTs), we proposed electronic health record-based clinical decision support for patient–clinician shared decision-making about care and RCT enrollment, based on “mathematical equipoise.”
As an example, we created the Knee Osteoarthritis Mathematical Equipoise Tool (KOMET) to determine the presence of patient-specific equipoise between treatments for the choice between total knee replacement (TKR) and nonsurgical treatment of advanced knee osteoarthritis.
With input from patients and clinicians about important pain and physical function treatment outcomes, we created a database from non-RCT sources of knee osteoarthritis outcomes. We then developed multivariable linear regression models that predict 1-year individual-patient knee pain and physical function outcomes for TKR and for nonsurgical treatment. These predictions allowed detecting mathematical equipoise between these two options for patients eligible for TKR. Decision support software was developed to graphically illustrate, for a given patient, the degree of overlap of pain and functional outcomes between the treatments and was pilot tested for usability, responsiveness, and as support for shared decision-making.
The KOMET predictive regression model for knee pain had four patient-specific variables, and an r2 value of 0.32, and the model for physical functioning included six patient-specific variables, and an r2 of 0.34. These models were incorporated into prototype KOMET decision support software and pilot tested in clinics, and were generally well received.
Use of predictive models and mathematical equipoise may help discern patient-specific equipoise to support shared decision-making for selecting between alternative treatments and considering enrollment into an RCT.
Despite the ubiquity of tunnel channels and valleys within formerly glaciated areas, their origin remains enigmatic. Few modern analogues exist for event-related subglacial erosion. This paper presents evidence of subglacial meltwater erosion and tunnel channel formation during the November 1996 jökulhlaup, Skeiðarárjökull, Iceland. The jökulhlaup reached a peak discharge of 45 000 to 50 000 m3 s–1, with flood outbursts emanating from multiple outlets across the entire 23 km wide glacier snout. Subsequent retreat of the southeast margin of Skeiðarárjökull has revealed a tunnel channel excavated into the surrounding moraine sediment and ascending 11.5m over a distance of 160 m from a larger trough to join the apex of an ice-contact fan formed in November 1996. The tunnel channel formed via hydro-mechanical erosion of 14 000m3 to 24 000 m3 of unconsolidated glacier substrate, evidenced by copious rip-up clasts within the ice-contact fan. Flow reconstruction provides peak discharge estimates of 680±140m3 s–1. The tunnel channel orientation, oblique to local ice flow direction and within a col, suggests that local jökulhlaup routing was controlled by (a) subglacial topography and (b) the presence of a nearby proglacial lake. We describe the first modern example of tunnel channel formation and illustrate the importance of pressurized subglacial jökulhlaup flow for tunnel channel formation.
British general incorporation law granted companies an extraordinary degree of contractual freedom. It provided companies with a default set of articles of association, but incorporators were free to reject any or all of the provisions and write their own rules instead. We study the uses to which incorporators put this flexibility by examining the articles of association filed by three random samples of companies from the late nineteenth and early twentieth centuries, as well as by a sample of companies whose securities traded publicly. Contrary to the literature, we find that most companies, regardless of size or whether their securities traded on the market, wrote articles that shifted power from shareholders to directors. We find, moreover, that there was little pressure from the government, shareholders, or the market to adopt more shareholder-friendly governance rules.
Risk adjustment is needed to fairly compare central-line–associated bloodstream infection (CLABSI) rates between hospitals. Until 2017, the Centers for Disease Control and Prevention (CDC) methodology adjusted CLABSI rates only by type of intensive care unit (ICU). The 2017 CDC models also adjust for hospital size and medical school affiliation. We hypothesized that risk adjustment would be improved by including patient demographics and comorbidities from electronically available hospital discharge codes.
Using a cohort design across 22 hospitals, we analyzed data from ICU patients admitted between January 2012 and December 2013. Demographics and International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) discharge codes were obtained for each patient, and CLABSIs were identified by trained infection preventionists. Models adjusting only for ICU type and for ICU type plus patient case mix were built and compared using discrimination and standardized infection ratio (SIR). Hospitals were ranked by SIR for each model to examine and compare the changes in rank.
Overall, 85,849 ICU patients were analyzed and 162 (0.2%) developed CLABSI. The significant variables added to the ICU model were coagulopathy, paralysis, renal failure, malnutrition, and age. The C statistics were 0.55 (95% CI, 0.51–0.59) for the ICU-type model and 0.64 (95% CI, 0.60–0.69) for the ICU-type plus patient case-mix model. When the hospitals were ranked by adjusted SIRs, 10 hospitals (45%) changed rank when comorbidity was added to the ICU-type model.
Our risk-adjustment model for CLABSI using electronically available comorbidities demonstrated better discrimination than did the CDC model. The CDC should strongly consider comorbidity-based risk adjustment to more accurately compare CLABSI rates across hospitals.
The ROSAT X-ray satellite mission and its X-ray telescope (XRT) are described by Trümper (1984). The characteristics of the Wide Field Camera (WFC) on ROSAT and its potential for studies of the soft X-ray background (SXRB) are discussed by Harris, Sumner, and Walker (1989, this volume). The energy range covered by the WFC is 0.06 keV to 0.21 keV (60 Å to 200 Å), whilst the XRT covers the higher energy range from 0.2 keV to 2 keV. Observations performed to date in this field have given rise to conflicting evidence on the location and nature of the 106 K gas, which is presumed to be the origin of the observed emission (see references in Harris, Sumner, and Walker, 1989, this volume).
The ROSAT X-ray astronomy satellite, due to be launched in early 1990, will carry two separate and complementary grazing-incidence telescopes with co-aligned axes. The German X-ray telescope (XRT) will cover the soft X-ray region in the range 0.15–2 keV (6–80 Å), while the U.K. XUV Wide Field Camera (WFC) will extend coverage to beyond 200 Å. The WFC is a joint project of Leicester and Birmingham Universities, the Mullard Space Science Laboratory, and the authors' institutes. The primary objective of ROSAT is to perform an all-sky survey over a period of six months. This will be followed by a guest-observer, “pointed” phase. We briefly discuss the sensitivity of the WFC to the soft X-ray/XUV background (SXRB) and the problems and techniques associated with distinguishing the astronomical background from other sources of background.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
The montane inselbergs of northern Mozambique have been comparatively little-studied, yet recent surveys have shown they have a rich biodiversity with numerous endemic species. Here we present the main findings from a series of scientific expeditions to one of these inselbergs, Mt Mabu, and discuss the conservation implications. Comprehensive species lists of plants, birds, mammals and butterflies are presented. The most significant result was the discovery of a c. 7,880 ha block of undisturbed rainforest, most of it at medium altitude (900–1,400 m), a forest type that is not well represented elsewhere. It is possibly the largest continuous block of this forest type in southern Africa. To date, 10 new species (plants, mammals, reptiles and butterflies) have been confirmed from Mt Mabu, even though sampling effort for most taxonomic groups has been low. The species assemblages indicate a relatively long period of isolation and many species found are at the southern limit of their range. Conservationists are now faced with the challenge of how best to protect Mt Mabu and similar mountains in northern Mozambique, and various ways that this could be done are discussed.
Compositional analyses were undertaken to evaluate the hypothesis that Shivwits Ware pottery found in southern Nevada was not produced in that area but, instead, manufactured on the Shivwits Plateau. The evidence supports this hypothesis and indicates that large quantities of Shivwits Ware jars moved through a distribution system linking the upland areas of the western Arizona Strip with the lowlands of southeastern Nevada. This long-distance movement of utilitarian pottery is unusual for precontact North America, in that it occurred in the apparent absence of any centralized distribution mechanisms and between what would have been small, kin-based communities. The nature and the causes for the development of this distribution system are discussed.
In 1999, I was a young postdoc moving to Syracuse University to work on LIGO, which had been a dream of mine since I was first introduced to gravitational wave detection as an undergraduate in Kip Thorne's class at Caltech. I had done my PhD in gravitational wave detection, but using the older technology of resonant masses rather than LIGO's laser inteferometry. I was concerned that my background would not prove appropriate. I soon found a common issue, thermal noise, that I was able to focus on. Beyond just a good fit for me, thermal noise was actually a topic in flux within LIGO at the time. A talented young theorist at Caltech named Yuri Levin had just shown that the optical coatings on the LIGO mirrors could well contribute much more thermal noise than anyone had anticipated. What was missing were realistic numbers to plug into Yuri's formulas to see just how big of an impact coating thermal noise might have. This became one of my principal roles in LIGO, as part of a group of experimentalists interested in this question at Stanford, Glasgow, as well as Syracuse and other collaborating institutions.
Since then, we in LIGO have found that coating thermal noise is a very important limit to sensitivity, and we have engaged in over a decade of theoretical, experimental, and modeling work to better understand and reduce it.