Tracking daily fatigue fluctuations in multiple sclerosis : ecological momentary assessment provides unique insights

The preparation of this manuscript was supported by a UK Economic and Social Research Council (ESRC) PhD studentship (ES/1026266/1) awarded to DP. The study was funded by the Psychology Unit at the University of Southampton. The authors declare that they have no conflict of interest. The authors thank all participants of this study. Open access via Springer Compact Agreement.Peer reviewedPublisher PD

A Brachistochrone Approach to Reconstruct the Inflaton Potential

We propose a new way to implement an inflationary prior to a cosmological dataset that incorporates the inflationary observables at arbitrary order. This approach employs an exponential form for the Hubble parameter $H(\phi)$ without taking the slow-roll approximation. At lowest non-trivial order, this $H(\phi)$ has the unique property that it is the solution to the brachistochrone problem for inflation.Comment: 13 pages, 2 figures, version matches published versio

How can we better prepare new doctors for the tasks and challenges of ward rounds?:An observational study of junior doctors' experiences

Founding: Economic and Social Research Council Open access via T&F agreement Acknowledgements The authors would like to thank participating FY1 doctors and the senior staff who made this study possible. Funding The study was funded by the ESRC via a Doctoral Studentship awarded to CB.Peer reviewedPublisher PD

Genome-wide variation and transcriptional changes in diverse developmental processes underlie the rapid evolution of seasonal adaptation

Many organisms enter a dormant state in their life cycle to deal with predictable changes in environments over the course of a year. The timing of dormancy is therefore a key seasonal adaptation, and it evolves rapidly with changing environments. We tested the hypothesis that differences in the timing of seasonal activity are driven by differences in the rate of development during diapause in Rhagoletis pomonella, a fly specialized to feed on fruits of seasonally limited host plants. Transcriptomes from the central nervous system across a time series during diapause show consistent and progressive changes in transcripts participating in diverse developmental processes, despite a lack of gross morphological change. Moreover, population genomic analyses suggested that many genes of small effect enriched in developmental functional categories underlie variation in dormancy timing and overlap with gene sets associated with development rate in Drosophila melanogaster. Our transcriptional data also suggested that a recent evolutionary shift from a seasonally late to a seasonally early host plant drove more rapid development during diapause in the early fly population. Moreover, genetic variants that diverged during the evolutionary shift were also enriched in putative cis regulatory regions of genes differentially expressed during diapause development. Overall, our data suggest polygenic variation in the rate of developmental progression during diapause contributes to the evolution of seasonality in R. pomonella. We further discuss patterns that suggest hourglass-like developmental divergence early and late in diapause development and an important role for hub genes in the evolution of transcriptional divergence

Macrosystems ecology: Understanding ecological patterns and processes at continental scales

Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sources of unexpected and novel behaviors in macrosystems. We present three examples that highlight the importance of this multiscaled systems perspective for understanding the ecology of regions to continents

Pragmatic evaluation of methods for retrieving unpublished information on comparator interventions in a systematic review of smoking cessation trials

Funding This work was funded by Cancer Research UK (application number C50862/A18446).Peer reviewe

Long-term results of open and endovascular revascularization of superficial femoral artery occlusive disease

BackgroundFirst-line treatment for patients with superficial femoral arterial (SFA) occlusive disease has yet to be determined. This study compared long-term outcomes between primary SFA stent placement and primary femoral-popliteal bypass. Periprocedural patient factors were examined to determine their effect on these results.MethodsAll femoral-popliteal bypasses and SFA interventions performed in consecutive patients with symptoms Rutherford 3 to 6 between 2001 and 2008 were reviewed. Time-dependent outcomes were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards were performed to determine predictors of graft patency. Multivariate analysis was completed to identify patient covariates most often associated with the primary therapy.ResultsA total of 152 limbs in 141 patients (66% male; mean age, 66 ± 22 years) underwent femoral-popliteal bypass, and 233 limbs in 204 patients (49% male; mean age, 70 ± 11 years) underwent SFA interventions. Four-year primary, primary-assisted, and secondary patency rates were 69%, 78%, and 83%, respectively, for bypass patients and 66%, 91%, and 95%, respectively, for SFA interventions. Six-year limb salvage was 80% for bypass vs 92% for stenting (P = .04). Critical limb ischemia (CLI) and renal insufficiency were predictors of bypass failure. Claudication was a predictor of success for SFA stenting. Three-year limb salvage rates for CLI patients undergoing surgery and SFA stenting were 83%. Amputation-free survival at 3 years for CLI patients was 55% for bypass and 59% for SFA interventions. Multivariate predictors (odds ratios and 95% confidence intervals) of covariates most frequently associated with first-line SFA stenting were TransAtlantic Inter-Society Consensus II A and B lesions (5.9 [3.4-9.1], P < .001), age >70 years (2.1 [1.4-3.1], P < .001), and claudication (1.7 [1.1-2.7], P = .01). Regarding bypass as first-line therapy, claudicant patients were more likely to have nondiabetic status (5.6 [3.3-9.4], P < .001), creatinine <1.8 mg/dL (4.6 [1.5-14.9], P = .01), age <70 years (2.7 [CI, 1.6-8.3], P < .001), and presence of an above-knee popliteal artery target vessel (1.9 [CI, 1.1-3.4] P = .02).ConclusionIndication, patient-specific covariates, and anatomic lesion classification have significant association when determining surgeon selection of SFA stenting or femoral-popliteal bypass as first-line therapy. Patients with SFA disease can have comparable long-term results when treatment options are well matched to patient-specific and anatomic characteristics

Induction of \u3cem\u3eIL19\u3c/em\u3e Expression through JNK and cGAS-STING Modulates DNA Damage–Induced Cytokine Production

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage–induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING–dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage