Longitudinal Data with Follow-up Truncated by Death: Finding a Match Between Analysis Method and Research Aims

Diverse analysis approaches have been proposed to distinguish data missing due to death from nonresponse, and to summarize trajectories of longitudinal data truncated by death. We demonstrate how these analysis approaches arise from factorizations of the distribution of longitudinal data and survival information. Models are illustrated using hypothetical data examples (cognitive functioning in older adults, and quality of life under hospice care) and up to 10 annual assessments of longitudinal cognitive functioning data for 3814 participants in an observational study. For unconditional models, deaths do not occur, deaths are independent of the longitudinal response, or the unconditional longitudinal response averages over the survival distribution. Unconditional models, such as random effects models, may implicitly impute data beyond the time of death. Fully conditional models stratify the longitudinal response trajectory by time of death. Fully conditional models are effective for describing individual trajectories, in terms of either aging (age, or years from baseline) or dying (years from death). Partly conditional models summarize the longitudinal response in the dynamic cohort of survivors. Partly conditional models are serial cross-sectional snapshots of the response. They reflect the average response in survivors at a given timepoint, rather than individual trajectories. Joint models of survival and longitudinal response describe the evolving health status of the entire cohort. Researchers using longitudinal data should consider which method of accommodating deaths is consistent with research aims, and use analysis methods accordingly

Incorporating Death into Health-Related Variables in Longitudinal Studies

Background: The aging process can be described as the change in health-related variables over time. Unfortunately, simple graphs of available data may be misleading if some people die, since they may confuse patterns of mortality with patterns of change in health. Methods have been proposed to incorporate death into self-rated health (excellent to poor) and the SF-36 profile scores, but not for other variables. Objectives: (1) To incorporate death into the following variables: ADLs, IADLs, mini-mental state examination, depressive symptoms, body mass index (BMI), blocks walked per week, bed days, hospitalization, systolic blood pressure, and the timed walk. (2) To discuss variables and settings for which this approach is helpful. (3) To use the approach to illustrate the effect of stroke on these variables. Setting: The Cardiovascular Health Study of 5,888 older adults, studied up to nine years. Mean age was 73 at baseline, and 658 had an incident stroke during follow-up. Methods: We categorized each variable, added a category for death, and examined stacked bar graphs over time. We dichotomized each variable into healthy/not healthy, assigning dead to the “not healthy” category, and calculated the probability of being healthy one year later, with the deaths set to zero. Trajectories for the 11 variables in the three years before and after an incident stroke were tabled and plotted. Other transformations were derived and discussed. Results: Graphs that did not account for death were too optimistic. Stroke had an adverse effect on all variables but systolic blood pressure (which improved) and BMI (which showed little change). The short-term effect of stroke was greatest on hospitalization, self-rated health, and IADLs. Alternative coding provided slightly different results. Conclusions: Categories or values for death can be added to a variety of longitudinal variables, permitting a description of an entire cohort’s trajectory over time. These transformations provide an additional approach for longitudinal studies of the health of older adults where some people die

Climate change and the kidney

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.Published versio

The first ever anti-football painting: A consideration of the soccer match in John Singer Sargent’s "Gassed"

The paper presents a discussion of Gassed, a large oil painting by John Singer Sargent displayed at the Imperial War Museum in London. Completed in 1919, Gassed is the major achievement from Sargent’s commission as an official war artist at the appointment of the British War Memorials Committee during the latter period of World War I. Prominent in the painting is a group of soldiers, blinded by a mustard gas attack, being lead to a casualty clearing station tent. In the distant background of the painting, another group of soldiers can be seen kitted out in football attire playing a match. The significance of this football imagery is our point of enquiry. As our title suggests, some recent interpretations regard the painting as offering critical reflection, from the time, about the symbolic links between sport and war. However, while the painting may certainly be left open to this type of viewer interpretation, archival and secondary resource material research does not support such a critical intention by the artist. Yet, nor is there evidence that Sargent’s intention was the projection of war-heroism. Rather, Sargent’s endeavour to faithfully represent what he observed allows Gassed to be regarded as a visual record of routine activity behind the lines and of football as an aspect of the daily life of British soldiers during the Great War

LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice

Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aβ. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aβ by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients

Subject Benchmark Statement: Forensic Science 2012

QAA subject benchmark statement for Forensic Scienc

Football: a counterpoint to the procession of pain on the Western Front, 1914-1918?

In this article, three artworks of the First World War containing images of recreational football are analysed. These three images, In the Wings of the Theatre of War, Artillery Men at Football and Gassed, span the war from its beginning to its conclusion and are discussed in relationship to the development of recreational football in the front-line area, the evolving policies of censorship and propaganda and in consideration of the national mood in Britain. The paper shows how football went from being a spontaneous and improvised pastime in the early stages of the war to a well organized entertainment by war’s end. The images demonstrate how the war was portrayed as a temporary affair by a confident nation in 1914 to a more resigned acceptance of a semi-permanent event to be endured by 1918; however, all three artworks show that the sporting spirit, and hence the fighting spirit, of the British soldier was intact

Evidence for impaired t cell dna methylation in systemic lupus erythematosus and rheumatoid arthritis

Procainamide and hydralazine inhibit T cell DNA methylation and induce autoreactivity in cloned CD4+ T cells. These drugs also induce an autoimmune syndrome, suggesting a possible relationship between DNA hypomethylation, T cell autoreactivity, and certain autoimmune diseases. To test this relationship, DNA methylation was studied in T cells from patients with rheumatoid arthritis and patients with systemic lupus erythematosus, and was found to be impaired. These results support a relationship between DNA hypomethylation and some forms of autoimmune disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37783/1/1780331109_ftp.pd

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman