Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study

UNLABELLED The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. INTRODUCTION This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

The Character of Christian-Muslim Encounter: Essays in Honour of David Thomas

The Character of Christian-Muslim Encounter is a Festschrift in honour of David Thomas, Professor of Christianity and Islam, and Nadir Dinshaw Professor of Inter Religious Relations, at the University of Birmingham, UK. The Editors have put together a collection of over 30 contributions from colleagues of Professor Thomas that commences with a biographical sketch and representative tribute provided by a former doctoral student, and comprises a series of wide-ranging academic papers arranged to broadly reflect three dimensions of David Thomas’ academic and professional work – studies in and of Islam; Christian-Muslim relations; the Church and interreligious engagement. These are set in the context of a focussed theme – the character of Christian-Muslim encounters – and cast within a broad chronological framework.

Extension of k-ratio methods to rank-based analyses

An extension of k-ratio multiple comparison methods to rank-based analyses is described. The new method is analogous to the Duncan-Godbold approximate k-ratio procedure for unequal sample sizes or correlated means. The close parallel of the new methods to the Duncan-Godbold approach is shown by demonstrating that they are based upon different parameterizations as starting points.^ A semi-parametric basis for the new methods is shown by starting from the Cox proportional hazards model, using Wald statistics. From there the log-rank and Gehan-Breslow-Wilcoxon methods may be seen as score statistic based methods.^ Simulations and analysis of a published data set are used to show the performance of the new methods. ^

Appendix A. Whole-rock major, trace and rare earth element analyses of the Ulubey volcanics, Appendix B. Analytical standards and detection limits for analyses

Collisional and post-collisional volcanic rocks in the Ulubey (Ordu) area at the western edge of the Eastern Pontide Tertiary Volcanic Province (EPTVP) in NE Turkey are divided into four suites; Middle Eocene (49.4-44.6 Ma) aged Andesite-Trachyandesite (AT), Trachyandesite-Trachydacite-Rhyolite (TTR), Trachydacite-Dacite (TD) suites, and Middle Miocene (15.1 Ma) aged Trachybasalt (TB) suite. Local stratigraphy in the Ulubey area starts with shallow marine environment sediments of the Paleocene-Eocene time and then continues extensively with sub-aerial andesitic to rhyolitic and rare basaltic volcanism during Eocene and Miocene time, respectively. Petrographically, the volcanic rocks are composed primarily of andesites/trachyandesites, with minor trachydacites/rhyolites, basalts/trachybasalts and pyroclastics, and show porphyric, hyalo-microlitic porphyric and rarely glomeroporphyric, intersertal, intergranular, fluidal and sieve textures. The Ulubey (Ordu) volcanic rocks indicate magma evolution from tholeiitic-alkaline to calc-alkaline with medium-K contents. Primitive mantle normalized trace element and chondrite normalized rare earth element (REE) patterns show that the volcanic rocks have moderate light rare earth element (LREE)/heavy rare earth element (HREE) ratios relative to E-Type MORB and depletion in Nb, Ta and Ti. High Th/Yb ratios indicate parental magma(s) derived from an enriched source formed by mixing of slab and asthenospheric melts previously modified by fluids and sediments from a subduction zone. All of the volcanic rocks share similar incompatible element ratios (e.g., La/Sm, Zr/Nb, La/Nb) and chondrite-normalized REE patterns, indicating that the basic to acidic rocks originated from the same source. The volcanic rocks were produced by the slab dehydration-induced melting of an existing metasomatized mantle source, and the fluids from the slab dehydration introduced significant large ion lithophile element (LILE) and LREE to the source, masking its inherent HFSE-enriched characteristics. The initial 87Sr/86Sr (0.7044-0.7050) and eNd (-0.3 to +3.4) ratios of the volcanics suggest that they originated from an enriched lithospheric mantle source with low Sm/Nd ratios. Integration of the geochemical, petrological and isotopical with regional and local geological data suggest that the Tertiary volcanic rocks from the Ulubey (Ordu) area were derived from an enriched mantle, which had been previously metasomatized by fluids derived from subducted slab during Eocene to Miocene in collisional and post-collisional extension-related geodynamic setting following Late Mesozoic continental collision between the Eurasian plate and the Tauride-Anatolide platform.

Physical oceanography and current velocity during Nathaniel B. Palmer cruise NBP97-05

An extensive set of conductivity-temperature-depth (CTD)/lowered acoustic Doppler current profiler (LADCP) data obtained within the northwestern Weddell Sea in August 1997 characterizes the dense water outflow from the Weddell Sea and overflow into the Scotia Sea. Along the outer rim of the Weddell Gyre, there is a stream of relatively low salinity, high oxygen Weddell Sea Deep Water (defined as water between 0° and ?0.7°C), constituting a more ventilated form of this water mass than that found farther within the gyre. Its enhanced ventilation is due to injection of relatively low salinity shelf water found near the northern extreme of Antarctic Peninsula's Weddell Sea shelf, shelf water too buoyant to descend to the deep-sea floor. The more ventilated form of Weddell Sea Deep Water flows northward along the eastern side of the South Orkney Plateau, passing into the Scotia Sea rather than continuing along an eastward path in the northern Weddell Sea. Weddell Sea Bottom Water also exhibits two forms: a low-salinity, better oxygenated component confined to the outer rim of the Weddell Gyre, and a more saline, less oxygenated component observed farther into the gyre. The more saline Weddell Sea Bottom Water is derived from the southwestern Weddell Sea, where high-salinity shelf water is abundant. The less saline Weddell Sea Bottom Water, like the more ventilated Weddell Sea Deep Water, is derived from lower-salinity shelf water at a point farther north along the Antarctic Peninsula. Transports of Weddell Sea Deep and Bottom Water masses crossing 44°W estimated from one LADCP survey are 25 ? 10**6 and 5 ? 10**6 m**3/s, respectively. The low-salinity, better ventilated forms of Weddell Sea Deep and Bottom Water flowing along the outer rim of the Weddell Gyre have the position and depth range that would lead to overflow of the topographic confines of the Weddell Basin, whereas the more saline forms may be forced to recirculate within the Weddell Gyre.

Pollen and spore deposition in different areas of the Lena Delta

Studies of the annual pollen and spore deposition in different areas of the Lena Delta were undertaken for the first time in the Asian sector of the Arctic during the Russian-German ''LENA 98'' and ''LENA 99'' expeditions in the framework of the International ''Laptev Sea System-2000'' Project. To achieve this objective, three spore-pollen traps were set up along the meridional delta profile in accordance with the European Pollen Monitoring Programme for the period July 1998 to August 1999. A comparison between the results of spore-pollen analysis of the contents of traps and the surrounding vegetation was performed. The results confirmed the current spore-pollen spectra are comprised both of pollen and spores of the local plants and of long-distance pollen and spores. The dependence of the long-distance pollen deposition on the character of the wind regime of the region was established. The prevailing southerly and southeasterly wind direction determines the main pollen influx of tree species from the areas of their growth south of the delta. The features of the morphological structure and fossilization of pollen and the features of the productive capability and plant growing conditions are of large significance in the pollen transfer and deposition.

Set of Matlab function to study geometrical parameters or channels

This set of functions allows one to compute the radius of curvature of a river in planform for the purpose of making correlations with other geometric parameters of a channel. The code may also be used to compute the width of a channel.

Hydrochemistry, phytoplankton pigment concentration and phytoplankton abundance in water samples obtained in the Kuroshio Extension Front in October 2009

This data was collected during a cruise to the Kuroshio Extension Front in October 2009. Several chemical and biological parameters were measured: dissolved nutrients, picophytoplankton (by flow cytometry), microphytoplankton (by light microscopy) and phytoplankton pigments (HPLC).