The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). The resource comprised 906,359 women and men (66.9
This paper studies how managers plan under uncertainty. In a new panel survey of German manufacturing firms, we observe both forecasts of sales growth and a quantitative measure of subjective uncertainty. We show that subjective uncertainty reflects change experienced by firms: It is high when growth is either unusually low or unusually high. Subjective uncertainty is more than conditional volatility; while more volatile firms are typically more uncertain, experienced change alone increases uncertainty, consistent with a model of learning. Uncertainty over our sample is mostly idiosyncratic but varies substantially over time and leads managers to plan lower employment and prices. (JEL C83, D22, E20, E23)
We investigate the locality number, a recently introduced structural parameter for strings (with applications in pattern matching with variables), and its connection to two important graph-parameters, cutwidth and pathwidth. These connections allow us to show that computing the locality number is -hard, but fixed-parameter tractable, if parameterised by the locality number or by the alphabet size, which has been formulated as open problems in the literature. Moreover, the locality number can be approximated with ratio O (√(log ( ))log (n)) . An important aspect of our work – that is relevant in its own right and of independent interest – is that we identify connections between the string parameter of the locality number on the one hand, and the famous graph parameters of cutwidth and pathwidth, on the other hand. These two parameters have been jointly investigated in the literature and are arguably among the most central graph parameters that are based on “linearisations” of graphs. In this way, we also identify a direct approximation preserving reduction from cutwidth to pathwidth, which shows that any polynomial f( ,|V|) -approximation algorithm for pathwidth yields a polynomial 2f(2 ,h) -approximation algorithm for cutwidth on multigraphs (where h is the number of edges). In particular, this translates known approximation ratios for pathwidth into new approximation ratios for cutwidth, namely O (√(log ( ))log (h)) and O (√(log ( )) ) for (multi) graphs with h edges.
The cause of the Frasnian-Famennian (F-F) boundary mass extinction, one of the largest Phanerozoic biocrises, remains uncertain. Here, we infer a short glaciation during the F-F transition based on evidence of sea-level fall and major changes in terrestrial inputs and weathering fluxes, suggesting that climatic cooling was the proximate cause of the F-F event. This study is based on an integrated elemental-isotopic-organic dataset from the West Valley core, representing prodelta facies of the Catskill Delta in western New York State. The 29-m-thick study interval records a shift from greenish-gray shales of the upper Hanover Formation to dark gray shales of the lower Dunkirk Formation that was accompanied by long-term increases in terrestrial organic and clay fluxes and more reducing watermass conditions. The 15-m interval bracketing the F-F boundary shows three shifts from near-marine (background) salinity to low-brackish conditions, implying that sea-level falls caused the study site to transiently shift into the basin's low-salinity surface-water layer. Superimposed on the general lithologic changes in this F-F transition section are twelve sedimentary cycles of similar to 1-5 m thickness (avg. 2.5 m) characterized by strong variation in TOC and most geochemical proxies. These cycles record climatic variation at an orbital (possibly similar to 18-kyr precessional) timescale, resulting in short-term fluctuations in sea level (as shown by salinity proxies) as well as in terrestrial organic and clastic fluxes (as reflected in organic and detrital proxies). Changes in sedimentary proxies at this short timescale show that the organic-rich layers were associated with more humid climatic conditions, higher sea-level stands (consistent with less continental ice mass), and more saline and reducing environmental conditions, whereas organic-poor layers were associated with drier climatic conditions, lower sea-level stands (consistent with more continental ice mass), and less saline and reducing environmental conditions. The F-F event, which spans seven such cycles, thus represents a comparatively short glacial episode with a duration of just similar to 126 +/- 18 kyr, although it is comparable to the more severe DevonianCarboniferous (D-C) boundary glaciation that heralded the onset of the Late Paleozoic Ice Age similar to 12 million years later. Both the F-F and D-C biocrises represent carbon-burial-type events and, although their ultimate cause(s) remain in debate, the existing observations favor a bioevolutionary mechanism linked to the evolution and spread of land plants.
BACKGROUND:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS:To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS:Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS:Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
