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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.
To sustain star formation rates (SFRs) of hundreds to thousands of solar masses per year over millions of years, a galaxy must efficiently cool its gas. At z ∼ 2, the peak epoch for stellar mass assembly, tracers of gas heating and cooling remain largely unexplored. For one z ∼ 2 starburst galaxy GS IRS20, we present Spitzer IRS spectroscopy of Polycyclic Aromatic Hydrocarbon (PAH) emission, and ALMA observations of [C II] 158 μm fine-structure emission which we use to probe ISM heating/cooling. Coupled with an unusually warm dust component, the ratio of [C II] /PAH emission suggests a low photolelectric efficiency, and/or the importance of cooling from other far-IR lines in this galaxy. A low photoelectric efficiency at z ∼ 2 could be key for the peak in the SFR density of the universe by decoupling stellar radiation from ISM gas temperatures.
A key outstanding issue in galaxy evolution studies is how galaxies quench their star formation. I will present new results from our VLT/X-Shooter, ALMA and VLA campaign of a pilot sample of lensed quiescent massive galaxies at z > 1.5. Lensing magnification enables us to spatially resolve the stellar structure and kinematics of these compact galaxies, that are otherwise barely resolvable even with HST. Our deep X-Shooter spectra provided multiple absorption lines enabling strong constraints on their stellar populations, namely their star formation rates, ages, dispersions, and in some cases metallicities. Our complementary ALMA+VLA programme probes their molecular gas content through CO emission. All these observations provide unparalleled constraints on their quenching mechanisms. Our results indicate that quiescent galaxies at z ∼ 2 (1) have short star formation timescales of a few hundred Myrs; (2) have a variety of stellar morphology from exponential disks to bulges; (3) are devoid of molecular gas; and (4) host low-luminosity active galactic nuclei which may be responsible for suppressing star formation. In addition to discussing the insights gained on quenching, I will highlight how these findings bring about new questions that can be addressed with future JWST and ALMA studies.
Climate change impacts on agriculture have been intensifying in the Northeastern United States. In order to encourage the adoption of climate change adaptation and mitigation practices by farmers, it is critical to understand their perspectives on the risks they face and actions they are taking. However, very few empirical studies have considered how farmers are interpreting and responding to climate impacts, risks and opportunities in the Northeast. This study investigates farmer views and decisions related to climate change using data from six farmer focus groups conducted across New York and Pennsylvania. The study examined how farmers perceived climate impacts on their farms, the practices they are willing to adopt, and how perceived risks and vulnerability affect farmers’ decision-making related to adaptation and mitigation strategies. Although farmers articulated concern regarding climate impacts, they also made clear that other business pressures, such as profitability, market conditions, labor availability or government regulations were often more critical issues that affected their decision-making. Decisions about adopting climate change adaptation and mitigation practices vary widely, and personal experience with extreme weather and changing seasons affected decision-making. The findings from this study provide improved understanding of farmers’ needs and priorities, which can help guide land-grant researchers, extension and policymakers in their efforts to develop and coordinate a comprehensive strategy to address climate change impacts on agriculture in the Northeast.
New medical technologies are an important part of delivering innovative healthcare, however, expanding use of medical technology is a major contributor to rising costs. The increase in medical spending is related to new technologies being rapidly developed, marketed and adopted; and often being incorporated into health systems with little evidence. They also come with higher prices when compared to existing technologies.
We describe how University of Washington (UW) Medicine has designed, and developed a new hospital-based health technology assessment (HB-HTA) program, Smart Innovation. Smart Innovation will replace a fragmented and complex set of purchasing and coverage-decision processes. The program will streamline the decision-making process for new medical technologies and balance quick turnaround with rigorous evidence standards. The program is also being developed in collaboration with UW Medicine's Value Analysis team, an evidence-based purchasing team and MedApproved, a new centralized software program for medical purchasing at UW Medicine.
Smart Innovation has been reviewing technologies during its first year and has received encouraging results. For example, by adopting a new liver ablation technology, UW Medicine has estimated improved patient outcomes by reducing the number of procedures and adverse events; as well as saving approximately USD 8,000 per patient. Additionally, The Smart Innovation program has achieved projected cost avoidance from deciding not to adopt uncertain or investigational technologies. For example, by not adopting a new bladder cancer screen, our models indicate UW Medicine will avoid spending USD 1.5 million per year.
Smart Innovation is proving to be an effective program for reviewing and making critical healthcare policy decisions that is showing significant fiscal and patient improvements for UW Medicine. As the program continues to grow and become embedded into UW Medicine, its impacts will become even more valuable and system-wide.
Allison P. Hobgood, Associate Professor of English and Women's and Gender Studies at Willamette University,
David Houston Wood, Distinguished Professor of English and Honors Program Director at Northern Michigan University
When we tell people that we work in early modern disability studies, they invariably respond, “Oh, you mean Richard III, right?” “Of course,” we reply, “but he's just the tip of the iceberg.” We open our essay with this anecdote not to invalidate its logic – the infamous Yorkist king is an obvious figure for examining disability in the late medieval and early modern periods – but to broaden our scopes of study and our literary imaginations when it comes to premodern disability and its representations. To that end, our chapter contributes to the growing body of work represented in this volume by articulating conceptions of disability specific to early modernity and theorizing the myriad ways disability operated (and was operationalized) in pre-Enlightenment England. We illuminate how varied embodiments and lived experiences of disabled individuals in the Renaissance functioned representationally in literature of the period and, further, cultivated unique aesthetic modes in early modern English texts. Our essay covers a wide array of genres – we explore well-known medico-philosophical treatises by Michel de Montaigne and Robert Burton alongside lesser known, noncanonical poetry and drama from the seventeenth century – to show both the diversity and ubiquity of Renaissance disability and its attendant literary discourses. The first part of our essay outlines some discourses of disability and their literary manifestations to reveal various “ideologies of ability” at work in the Renaissance. The second section offers a case study in which we engage early modern humoral theory as one way bodily dys/function was configured in the sixteenth and seventeenth centuries. Part three explores how, on both the page and stage, early modern disability generates what contemporary disability theorists have called a disability aesthetic, in this case, a compelling ethical and aesthetic desire for disability produced by the performance of impairment on the English Renaissance stage.
Early Modern Ideologies of Ability
In his seminal study, Disability Theory, Tobin Siebers aims to “define the ideology of ability and to make its workings legible and familiar, despite how imbricated it may be in our thinking and practices, and despite how little we notice its patterns, authority, contradictions, and influence as a result.
The focus of this commentary is Nettle et al.'s insurance hypothesis linking food insecurity to a high body mass index (BMI). We discuss how the relationship between race/ethnicity and obesity in the United States is consistent with this hypothesis, then present potential ways forward to elucidate the validity of this hypothesis in humans through rigorous controlled trials.
To measure transmission frequencies and risk factors for household acquisition of community-associated and healthcare-associated (HA-) methicillin-resistant Staphylococcus aureus (MRSA).
Prospective cohort study from October 4, 2008, through December 3, 2012.
Seven acute care hospitals in or near Toronto, Canada.
Total of 99 MRSA-colonized or MRSA-infected case patients and 183 household contacts.
Baseline interviews were conducted, and surveillance cultures were collected monthly for 3 months from household members, pets, and 8 prespecified high-use environmental locations. Isolates underwent pulsed-field gel electrophoresis and staphylococcal cassette chromosome mec typing.
Overall, of 183 household contacts 89 (49%) were MRSA colonized, with 56 (31%) detected at baseline. MRSA transmission from index case to contacts negative at baseline occurred in 27 (40%) of 68 followed-up households. Strains were identical within households. The transmission risk for HA-MRSA was 39% compared with 40% (P=.95) for community-associated MRSA. HA-MRSA index cases were more likely to be older and not practice infection control measures (P=.002–.03). Household acquisition risk factors included requiring assistance and sharing bath towels (P=.001–.03). Environmental contamination was identified in 78 (79%) of 99 households and was more common in HA-MRSA households.
Household transmission of community-associated and HA-MRSA strains was common and the difference in transmission risk was not statistically significant.
To investigate relationships between mortality and circulating 25-hydroxyvitamin D (25(OH)D), 25-hydroxycholecalciferol (25(OH)D3) and 25-hydroxyergocalciferol (25(OH)D2).
Case–cohort study within the Melbourne Collaborative Cohort Study (MCCS). We measured 25(OH)D2 and 25(OH)D3 in archived dried blood spots by LC–MS/MS. Cox regression was used to estimate mortality hazard ratios (HR), with adjustment for confounders.
The MCCS included 29 206 participants, who at recruitment in 1990–1994 were aged 40–69 years, had dried blood spots collected and no history of cancer. For the present study we selected participants who died by 31 December 2007 (n 2410) and a random sample (sub-cohort, n 2996).
The HR per 25 nmol/l increment in concentration of 25(OH)D and 25(OH)D3 were 0·86 (95 % CI 0·78, 0·96; P=0·007) and 0·85 (95 % CI 0·77, 0·95; P=0·003), respectively. Of 5108 participants, sixty-three (1·2 %) had detectable 25(OH)D2; their mean 25(OH)D concentration was 11·9 (95 % CI 7·3, 16·6) nmol/l higher (P<0·001). The HR for detectable 25(OH)D2 was 1·80 (95 % CI 1·09, 2·97; P=0·023); for those with detectable 25(OH)D2, the HR per 25 nmol/l increment in 25(OH)D was 1·06 (95 % CI 0·87, 1·29; P interaction=0·02). HR were similar for participants who reported being in good, very good or excellent health four years after recruitment.
Total 25(OH)D and 25(OH)D3 concentrations were inversely associated with mortality. The finding that the inverse association for 25(OH)D was restricted to those with no detectable 25(OH)D2 requires confirmation in populations with higher exposure to ergocalciferol.
Material previously referred to as Cassubia infercambriensis was re-examined and found to represent a composite fossil of a Peytoia-like anomalocaridid frontal appendage and an arthropod of uncertain affinities comparable to some bivalved arthropod taxa. The frontal appendage is referred to the genus Peytoia based on the presence of elongated ventral spines bearing a single row of auxiliary spines. As well as representing the oldest example of an anomalocaridid in the fossil record (Series 2, Stage 3), Peytoia infercambriensis is also the only record of this group from the East European Craton, therefore extending both the temporal and geographic range of the anomalocaridid family Hurdiidae.
Anxiety often co-occurs with major depressive disorder (MDD). This preliminary study sought to ascertain the extent to which anxious depression drives group neurobiological differences between patients with MDD and healthy volunteers (HVs).
Magnetoencephalography beta-band frequency was used to compare differences in brain response during the N-back working memory task between 30 medication-free patients with treatment-resistant MDD (anxious depression=18; nonanxious depression=12) and 28 HVs.
Compared to HVs, patients with anxious depression had significantly reduced desynchronisation (less activation) in the left precuneus, right cuneus, and left insula extending into the inferior and middle frontal cortex during the 2-back condition compared with the 1-back condition of the N-back working memory task – indicating less activation of these neural networks in patients with anxious depression during the condition with the highest level of task demands. No other significant group differences were found during the working memory conditions.
This preliminary study suggests that a subset of patients – those with anxious depression – may be driving observed group differences between patients with MDD and HVs. Further neurobiological studies and replication experiments are necessary to determine the extent to which this subgroup has preferentially influenced our understanding of the underlying neurobiology of depression.
Patients with damage to the cerebellum make reaching movements that are uncoordinated or “ataxic.” One prevailing hypothesis is that the cerebellum functions as an internal model for planning movements, and that damage to the cerebellum results in movements that do not properly account for arm dynamics. An exoskeleton robot was used to record multi-joint reaching movements. Subsequently, joint-torque trajectories were calculated and a gradient descent algorithm found optimal, patient-specific perturbations to actual limb dynamics predicted to reduce directional reaching errors by an average of 41%, elucidating a promising form of robotic intervention and adding support to the internal model hypothesis.
There is continuing debate about long-term effects of brain injury. We examined a range of traumatic brain injury (TBI) variables (TBI history, severity, frequency, and age of injury) as predictors of cognitive outcome over 8 years in an adult population, and interactions with apolipoprotein E (APOE) genotype, sex, and age cohorts. Three randomly sampled age cohorts (20–24, 40–44, 60–64 years at baseline; N = 6333) were each evaluated three times over 8 years. TBI variables, based on self-report, were separately modeled as predictors of cognitive performance using linear mixed effects models. TBI predicted longitudinal cognitive decline in all three age groups. APOE ε4+ genotypes in the young and middle-aged groups predicted lower baseline cognitive performance in the context of TBI. Baseline cognitive performance was better for young females than males but this pattern reversed in middle age and old age. The findings suggest TBI history is associated with long-term cognitive impairment and decline across the adult lifespan. A role for APOE genotype was apparent in the younger cohorts but there was no evidence that it is associated with impairment in early old age. The effect of sex and TBI on cognition varied with age cohort, consistent with a proposed neuroprotective role for estrogen. (JINS, 2014, 20, 444–454)
This study examined interdependent trajectories of sexual risk, substance use, and conduct problems among 12- to 18-year-old African American youths who were followed annually as part of the Mobile Youth Study. We used growth mixture modeling to model the development of these three outcomes in the 1,406 participants who met the inclusion criteria. Results indicate that there were four distinct classes: normative, low risk (74.3% of sample); increasing high-risk takers (11.9%); adolescent-limited conduct problems and drug risk with high risky sex (8.0%); and early experimenters (5.8%) The higher risk classes had higher rates of pregnancy and sexually transmitted infections diagnoses than the normative sample at each of the ages we examined. Differing somewhat from our hypothesis, all of the nonnormative classes exhibited high sexual risk behavior. Although prevention efforts should be focused on addressing all three risk behaviors, the high rate of risky sexual behavior in the 25% of the sample that fall into the three nonnormative classes underscores an urgent need for improved sex education, including teen pregnancy and HIV/sexually transmitted infections prevention, in this community.