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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
In 2017, Public Health England South East Health Protection Team (HPT) were involved in the management of an outbreak of Mycobacterium bovis (the causative agent of bovine tuberculosis) in a pack of working foxhounds. This paper summarises the actions taken by the team in managing the public health aspects of the outbreak, and lessons learned to improve the management of future potential outbreaks. A literature search was conducted to identify relevant publications on M. bovis. Clinical notes from the Public Health England (PHE) health protection database were reviewed and key points extracted. Animal and public health stakeholders involved in the management of the situation provided further evidence through unstructured interviews and personal communications. The PHE South East team initially provided ‘inform and advise’ letters to human contacts whilst awaiting laboratory confirmation to identify the infectious agent. Once M. bovis had been confirmed in the hounds, an in-depth risk assessment was conducted, and contacts were stratified in to risk pools. Eleven out of 20 exposed persons with the greatest risk of exposure were recommended to attend TB screening and one tested positive, but had no evidence of active TB infection. The number of human contacts working with foxhound packs can be large and varied. HPTs should undertake a comprehensive risk assessment of all potential routes of exposure, involve all other relevant stakeholders from an early stage and undertake regular risk assessments. Current guidance should be revised to account for the unique risks to human health posed by exposure to infected working dogs.
Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
Surgical site infections (SSIs) following colorectal surgery (CRS) are among the most common healthcare-associated infections (HAIs). Reduction in colorectal SSI rates is an important goal for surgical quality improvement.
To examine rates of SSI in patients with and without cancer and to identify potential predictors of SSI risk following CRS
American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data files for 2011–2013 from a sample of 12 National Comprehensive Cancer Network (NCCN) member institutions were combined. Pooled SSI rates for colorectal procedures were calculated and risk was evaluated. The independent importance of potential risk factors was assessed using logistic regression.
Of 22 invited NCCN centers, 11 participated (50%). Colorectal procedures were selected by principal procedure current procedural technology (CPT) code. Cancer was defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes.
The primary outcome of interest was 30-day SSI rate.
A total of 652 SSIs (11.06%) were reported among 5,893 CRSs. Risk of SSI was similar for patients with and without cancer. Among CRS patients with underlying cancer, disseminated cancer (SSI rate, 17.5%; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.23–2.26; P=.001), ASA score ≥3 (OR, 1.41; 95% CI, 1.09–1.83; P=.001), chronic obstructive pulmonary disease (COPD; OR, 1.6; 95% CI, 1.06–2.53; P=.02), and longer duration of procedure were associated with development of SSI.
Patients with disseminated cancer are at a higher risk for developing SSI. ASA score >3, COPD, and longer duration of surgery predict SSI risk. Disseminated cancer should be further evaluated by the Centers for Disease Control and Prevention (CDC) in generating risk-adjusted outcomes.
A new snow—soil—vegetation—atmosphere transfer (Snow-SVAT) scheme, which simulates the accumulation and ablation of the snow cover beneath a forest canopy, is presented. The model was formulated by coupling a canopy optical and thermal radiation model to a physically based multi-layer snow model. This canopy radiation model is physically based yet requires few parameters, so can be used when extensive in situ field measurements are not available. Other forest effects such as the reduction of wind speed, interception of snow on the canopy and the deposition of litter were incorporated within this combined model, SNOWCAN, which was tested with data taken as part of the Boreal Ecosystem—Atmosphere Study (BOREAS) international collaborative experiment. Snow depths beneath four different canopy types and at an open site were simulated. Agreement between observed and simulated snow depths was generally good, with correlation coefficients ranging between r2 = 0.94 and r2 = 0.98 for all sites where automatic measurements were available. However, the simulated date of total snowpack ablation generally occurred later than the observed date. A comparison between simulated solar radiation and limited measurements of sub-canopy radiation at one site indicates that the model simulates the sub-canopy downwelling solar radiation early in the season to within measurement uncertainty.
On an 11 m firn/ice core from Kongsvegen, Svalbard, we have used dielectric profiling (DEP) to measure electrical properties, and digital photography to measure a core optical stratigraphy (COS) profile. We also used a neutron-scattering probe (NP) to measure a density profile in the borehole from which the core was extracted. The NP- and DEP-derived density profiles were similar, showing large-scale (>30 cm) variation in the gravimetric densities of each core section. Fine-scale features (<10 cm) are well characterized by the COS record and are seen at a slightly lower resolution in both the DEP and NP records, which show increasing smoothing. A combination of the density accuracy of NP and the spatial resolution of COS provides a useful method of evaluating the shallow-density profile of a glacier, improving paleoclimate interpretation, mass-balance measurement and interpretation of radar returns.
Over the period 1972–98 the height of the snow surface at eight Antarctic sites in Palmer Land and on Alexander Island has been measured with respect to fixed points on local nunataks. From these data an empirical relation between height changes over a given period and three key variables has been derived. These variables are (i) the local mean annual surface air temperature, (ii) a regional estimate of energy available for melt over the period (derived from the nearby Rothera air-temperature record) and (iii) a regional estimate of accumulation over the period (derived from the nearby Gomez Nunatak ice-core accumulation record). Using this relation, the contribution of the Antarctic Peninsula to sea-level rise for warming from climatic conditions (averaged over the last 30 years) is estimated to be −0.006 ± 0.002 mm a−1 K−1. If recent warm conditions persist, however, and meltwater can run off to the sea, the contribution to sea-level rise from ablation is calculated to be 0.07 ± 0.02 mm a−1 K−1.
We have determined accumulation histories by identifying annual-layer horizons in records obtained by three independent methods: (1) glaciochemical analysis on a core, (2) density profiling in the borehole from which the core was taken, using the neutron-probe (NP) technique, and (3) borehole optical stratigraphy (BOS), again in the same borehole. We also used three different techniques for determining density to convert annual-layer thickness to accumulation: (1) gravimetric measurements on core samples, (2) measurement of density using NP and (3) a simple empirical model based on regional climatology. The result is nine different accumulation time series, three of which are completely independent. The chemical-analysis- and NP-derived accumulation time series are correlated, and the ∼70 year means are in agreement. The BOS-derived accumulation ∼70 year mean is slightly lower, probably due to a combination of the empirical density model’s underestimate of the density profile and the misidentification of sub-annual events in the shallow part of the borehole as annual horizons.
We have made side-by-side measurements in several boreholes at Summit, Greenland, using borehole optical stratigraphy (BOS) and neutron-scattering density logging techniques. The BOS logs show strong positive correlation at shallow depths with neutron-scattering logs taken in the same borehole. This supports the hypothesis that BOS detects changes in density. The positive correlation between returned brightness and density decreases with depth and finally becomes negative. We conclude this inversion of correlation is related to changes in densification regime from grain-boundary sliding to pressure sintering.
Although trophic position or level is one of the most basic aspects of a benthic marine species' ecology, its evolutionary significance remains obscure. Gastropods offer a suitable model for examining the relationship between trophic level and evolution since they exhibit a wide variety of trophic strategies and their mode of life is often reflected in their shell form. We examined 196 genera of Paleozoic gastropods (≈ 1/3 of known genera) for which first appearance and last appearance could be specified to stage level and for which trophic strategy could be inferred with a reasonable degree of confidence. We classified these genera into four trophic categories on the basis of shell characters relating to locomotion and clamping. These trophic categories are: Suspension feeders, Grazers on firm substrata, Soft substrate Grazers/Detritivores, and Carnivores. Suspension feeders are the most unambiguously recognizable category, marked by clear indicators of a sessile mode of life such as a radial apertures and planispiral shell forms. Our central observation from these data is that suspension feeders have shorter generic longevities than the other three trophic groups. This pattern is robust to a variety of methods of analysis. The mean generic longevity of the suspension feeders is 15 MY less than the other trophic categories. Cumulative frequency of genera within trophic categories versus log duration shows suspension feeders to be statisticaly significantly shorter lived than the other three trophic categories. The other three categories are not distinguishable. This pattern is unchanged by the removal of taxa dying out at mass extinctions. Suspension feeders have lower origination rates and higher extinction rates than the other trophic classes. This is not a taxonomic artifact produced by ornamentation and the number of characters available. This background pattern is also present in the end Ordovician and Late Devonian mass extinctions. Suspension feeders loose about half their genera in these extinctions, the two classes of grazers loose about 1/3 of their genera, and the carnivores suffer almost no extinctions. Suspension feeding appears to carry a significant evolutionary detriment in both mass extinctions and background times. This may be reflected in the change in trophic distribution of gastropods from the Ordovician to the Recent. The end Permian extinction shows a different pattern of selectivity; detritivores suffer the least.
For the first time, valence electron energy-loss spectroscopy (VEELS) was applied to individual single-crystalline SnO2 nanowires to investigate the dielectric function, band gap, and optical absorption coefficient. The results are compared with data from optical techniques such as spectroscopic ellipsometry and UV-Vis, and theoretical calculations from variations of density functional theory. The data obtained agree well with the standard optical and theoretical techniques. The dielectric function and optical absorption coefficient are given up to 20 eV, which otherwise requires a synchrotron source and large single crystals via optical methods. The energy loss function is given up to 40 eV, which gives a useful comparison to previous theoretical studies in an energy range that cannot be achieved via optical measurements. The comparison gives confidence in the accuracy of this method for exploring spatially-resolved measurements in individual nanoparticles or more complex nanostructures that are otherwise difficult to measure accurately using optical techniques.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
Background: Oncotype DX (ODX), a tumor gene profiling test, has been incorporated into clinical guidelines to aid in adjuvant chemotherapy decision making for early-stage, hormone receptor positive breast cancer patients. Despite United States (U.S.) guidelines, less than half of eligible women receive testing. Reasons for low usage are unclear: Our objective was to better understand U.S. oncologists’ ODX uptake and how they use ODX during adjuvant chemotherapy decision making.
Methods: We conducted semi-structured, ~30-minute phone interviews with medical and surgical oncologists in one U.S. State using purposive sampling. Oncologists were included if they saw greater than or equal to five breast cancer patients per week. Recruitment ended upon thematic saturation. Interviews were recorded, transcribed, and double-coded using template analysis.
Results: During analysis, themes emerged across three domains. First, organizational factors (i.e., departmental structure, ODX marketing, and medical/insurance guidelines) influenced ease of ODX use. Second, oncologists referenced the influence of interpersonal factors (e.g., normative beliefs and peer use of ODX) over their own practices and recommendations. Third, intrapersonal factors (e.g., oncologist attitudes, perceived barriers, and research gaps) were discussed: although oncologists largely held positive attitudes about ODX, they reported challenges with interpreting intermediate scores for treatment decisions and explaining test results to patients. Finally, oncologists identified several research gaps.
Conclusions: As more tumor gene profiling tests are incorporated into cancer care for treatment decision making, it is important to understand their use in clinical practice. This study identified multi-level factors that influence ODX uptake into clinical practice, providing insights into facilitators and modifiable barriers that can be leveraged for improving ODX uptake to aid treatment decision making.
The castles of the late medieval period represent some of the finest medieval monuments in Britain, with an almost infinite capacity to fascinate and draw controversy. They are also a source of considerable academic debate. The contents of this volume represent key works in castle scholarship. Topics discussed include castle warfare, fortress customs, architectural design and symbolism, spatial planning and the depiction of castles in medieval romance. The contributions also serve to highlight the diversity of approaches to the medieval castle, ranging from the study of documentary and literary sources, analysis of fragmentary architectural remains and the recording of field archaeology. The result is a survey that offers an in-depth analysis of castle building from the thirteenth to the fifteenth centuries, and places castles within their broader social, architectural and political contexts.
Robert Liddiard is Professor of History, University of East Anglia.
Contributors: Nicola Coldstream, Charles Coulson, Philip Dixon, Graham Fairclough, P.A. Faulkner, John Goodall, Beryl Lott, Charles McKean, T.E. McNeill, Richard K. Morris, Michael Prestwich, Christopher Taylor, Muriel A. Whitaker.