Model selection for prognostic time-to-event gene signature discovery with applications in early breast cancer data

Model selection between competing models is a key consideration in the discovery of prognostic multigene signatures. The use of appropriate statistical performance measures as well as verification of biological significance of the signatures is imperative to maximise the chance of external validation of the generated signatures. Current approaches in time-to-event studies often use only a single measure of performance in model selection, such as logrank test p-values, or dichotomise the follow-up times at some phase of the study to facilitate signature discovery. In this study we improve the prognostic signature discovery process through the application of the multivariate partial Cox model combined with the concordance index, hazard ratio of predictions, independence from available clinical covariates and biological enrichment as measures of signature performance. The proposed framework was applied to discover prognostic multigene signatures from early breast cancer data. The partial Cox model combined with the multiple performance measures were used in both guiding the selection of the optimal panel of prognostic genes and prediction of risk within cross validation without dichotomising the follow-up times at any stage. The signatures were successfully externally cross validated in independent breast cancer datasets, yielding a hazard ratio of 2.55 [1.44, 4.51] for the top ranking signature.</p

Development of GERAS DANcing for Cognition and Exercise (DANCE) : a feasibility study

Background: Dance is a mind-body activity of purposeful rhythmic movement to music. There is growing interest in using dance as a form of cognitive and physical rehabilitation. This manuscript describes the development of GERAS DANcing for Cognition and Exercise (DANCE) and evaluates its feasibility in older adults with cognitive and mobility impairments. Methods: The progressive dance curricula were delivered for 15 weeks (1-h class; twice weekly). Participants were eligible if they were community-dwelling older adults aged 60+ with early cognitive or mobility impairment able to follow three-step commands and move independently. Feasibility outcomes included recruitment/retention, adherence, participant satisfaction, safety, and adverse events. Results: Twenty-fve older adults (mean (standard deviation [SD]) age=77.55 (6.10) years, range 68–90 years) with early cognitive (Montreal Cognitive Assessment score (SD)=21.77 (4.05)) and mobility (92% were pre-frail/frail as indicated on the Fried Frailty Phenotype) impairments were recruited from a geriatric out-patient clinic or within the community. A total of 20/25 (80%) participants completed the study. Average class attendance was 72%, and self-reported homework adherence “most-days / every day” was 89%. A stepwise progression in the dance curricula was observed with increases in motor complexity and balance demands, and 95% of participants rated the program as a “just-right” challenge. Ninety percent of participants rated GERAS DANCE as excellent, and 100% would recommend the program to a friend or family member. Over 50% of participants connected outside of class time for a self-initiated cofee club. Adverse events of falls and fractures were reported for 2 participants, which occurred at home unrelated to the dance intervention during the study period. Pre-determined thresholds for feasibility were met for all outcomes. Discussion: GERAS DANCE is a feasible and enjoyable program for older adults with early cognitive or mobility impairments. GERAS DANCE curriculum grading (duration; sequence; instructions) and motor complexity increases in agility, balance, and coordination appear appropriately tailored for this population. Future work will explore the feasibility of GERAS DANCE in new settings (i.e., virtually online, community centers, or retirement homes) and the mind-body-social benefts of dance

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

A programme to spread eGFR graph surveillance for the early identification, support and treatment of people with progressive chronic kidney disease (ASSIST-CKD): protocol for the stepped wedge implementation and evaluation of an intervention to reduce late presentation for renal replacement therapy

Background Patients who start renal replacement therapy (RRT) for End-Stage Kidney Disease (ESKD) without having had timely access to specialist renal services have poor outcomes. At one NHS Trust in England, a community-wide CKD management system has led to a decline in the incident rate of RRT and the lowest percentage of patients presenting within 90 days of starting RRT in the UK. We describe the protocol for a quality improvement project to scale up and evaluate this innovation. Methods The intervention is based upon an off-line database that integrates laboratory results from blood samples taken in all settings stored under different identifying labels relating to the same patient. Graphs of estimated glomerular filtration rate (eGFR) over time are generated for patients 65 years with an incoming eGFR <40 ml/min/1.73 m2. Graphs where kidney function is deteriorating are flagged by a laboratory scientist and details sent to the primary care doctor (GP) with a prompt that further action may be needed. We will evaluate the impact of implementing this intervention across a large population served by a number of UK renal centres using a mixed methods approach. We are following a stepped-wedge design. The order of implementation among participating centres will be randomly allocated. Implementation will proceed with unidirectional steps from control group to intervention group until all centres are generating graphs of eGFR over time. The primary outcome for the quantitative evaluation is the proportion of patients referred to specialist renal services within 90 days of commencing RRT, using data collected routinely by the UK Renal Registry. The qualitative evaluation will investigate facilitators and barriers to adoption and spread of the intervention. It will include: semi-structured interviews with laboratory staff, renal centre staff and service commissioners; an online survey of GPs receiving the intervention; and focus groups of primary care staff. Discussion Late presentation to nephrology for patients with ESKD is a source of potentially avoidable harm. This protocol describes a robust quantitative and qualitative evaluation of a quality improvement intervention to reduce late presentation and improve the outcomes for patients with ESKD

Galaxy and Mass Assembly (GAMA): the wavelength dependence of galaxy structure versus redshift and luminosity

We study how the sizes and radial profiles of galaxies vary with wavelength, by fitting Se´rsic functions simultaneously to imaging in nine optical and near-infrared bands. To quantify the wavelength dependence of effective radius we use the ratio, R, of measurements in two rest- frame bands. The dependence of Se´rsic index on wavelength, N , is computed correspondingly. Vulcani et al. have demonstrated that different galaxy populations present sharply contrasting behaviour in terms of R and N . Here we study the luminosity dependence of this result. We find that at higher luminosities, early-type galaxies display a more substantial decrease in effective radius with wavelength, whereas late types present a more pronounced increase in Se´rsic index. The structural contrast between types thus increases with luminosity. By considering samples at different redshifts, we demonstrate that lower data quality reduces the apparent difference between the main galaxy populations. However, our conclusions remain robust to this effect. We show that accounting for different redshift and luminosity selections partly reconciles the size variation measured by Vulcani et al. with the weaker trends found by other recent studies. Dividing galaxies by visual morphology confirms the behaviour inferred using morphological proxies, although the sample size is greatly reduced. Finally, we demonstrate that varying dust opacity and disc inclination can account for features of the joint distribution of R and N for late-type galaxies. However, dust does not appear to explain the highest values of R and N . The bulge–disc nature of galaxies must also contribute to the wavelength dependence of their structure. Key words: galaxies: formation – galaxies: fundamental parameters – galaxies: general – galaxies: structure

mTORC1 underlies ageâ related muscle fiber damage and loss by inducing oxidative stress and catabolism

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these ageâ related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1’s activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3’s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to ageâ related muscle atrophy, and GDF signaling is a proposed mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/1/acel12943-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/2/acel12943.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/3/acel12943-sup-0001-FigS1-S14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/4/acel12943_am.pd

Madagascar corals track sea surface temperature variability in the Agulhas Current core region over the past 334 years

The Agulhas Current (AC) is the strongest western boundary current in the Southern Hemisphere and is key for weather and climate patterns, both regionally and globally. Its heat transfer into both the midlatitude South Indian Ocean and South Atlantic is of global significance. A new composite coral record (Ifaty and Tulear massive Porites corals), is linked to historical AC sea surface temperature (SST) instrumental data, showing robust correlations. The composite coral SST data start in 1660 and comprise 200 years more than the AC instrumental record. Numerical modelling exhibits that this new coral derived SST record is representative for the wider core region of the AC. AC SSTs variabilities show distinct cooling through the Little Ice Age and warming during the late 18th, 19th and 20th century, with significant decadal variability superimposed. Furthermore, the AC SSTs are teleconnected with the broad southern Indian and Atlantic Oceans, showing that the AC system is pivotal for inter-ocean heat exchange south of Africa

The Decline of Remarriage: Evidence From German Village Populations in the Eighteenth and Nineteenth Centuries

Family reconstitution data for fourteen German village populations permit the examination of remarriage during the eighteenth and nineteenth cen turies. The results provide compelling evidence for a secular decline in the tenden cy to remarry. Pronounced age and sex differentials in the likelihood of remar riage were evident: widows were far less likely to remarry than widowers, and the probability of remarriage declined rapidly with age, particularly for women. The probability of remarriage was also inversely associated with the number and age of children. There were, however, no clear differences in either the probability of remarriage or its tendency to decline over time among major occupational groups. The decline in remarriage probabilities was caused in part by declines in adult mortality, which gradually raised the ages of surviving spouses to levels at which remarriage has historically been rather unlikely. However, age-specific marriage probabilities also declined, affecting both men and women and all oc cupational groups, suggesting the presence of a social change of wide scope. Some comments on possible factors contributing to the decline of remarriage are presented. The need for a comprehensive explanation of remarriage trends and differentials remains an important challenge for family historians.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68212/2/10.1177_036319908501000103.pd

Preferences for the Sex of Offspring and Demographic Behavior in Eighteenth- and Nineteenth-Century Germany: an Examination of Evidence From Village Genealogies

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68167/2/10.1177_036319908000500202.pd