Longitudinal extension of myelomalacia by intramedullary and subdural hemorrhage in a canine model of spinal cord injury

BACKGROUND CONTEXT In canine intervertebral disc (IVD) extrusion, a spontaneous animal model of spinal cord injury, hemorrhage is a consistent finding. In rodent models, hemorrhage might be involved in secondary tissue destruction by biochemical mechanisms. PURPOSE This study aimed to investigate a causal association between the extents of intramedullary, subdural and epidural hemorrhage and the severity of spinal cord damage following IVD extrusion in dogs. STUDY DESIGN/SETTING A retrospective study using histologic spinal cord sections from 83 dogs euthanized following IVD extrusion was carried out. METHODS The degree of hemorrhage (intramedullary, subdural, epidural), the degree of spinal cord damage in the epicenter (white and gray matter), and the longitudinal extent of myelomalacia were graded. Associations between the extent of hemorrhage and the degree of spinal cord damage were evaluated statistically. RESULTS Intramedullary and subdural hemorrhages were significantly associated with the degree of white (p<.001/ p=.004) and gray (both p<.001) matter damage, and with the longitudinal extension of myelomalacia (p<.001/p=.005). Intriguingly, accumulation of hemorrhagic cord debris inside or dorsal to a distended and ruptured central canal in segments distant to the epicenter of the lesion was observed exhibiting a wave-like pattern on longitudinal assessment. The occurrence of this debris accumulation was associated with high degrees of tissue destruction (all p<.001). CONCLUSIONS Tissue liquefaction and increased intramedullary pressure associated with hemorrhage are involved in the progression of spinal cord destruction in a canine model of spinal cord injury and ascending or descending myelomalacia. Functional and dynamic studies are needed to investigate this concept further.

Distributed transpressive continental deformation: The Varto Fault Zone, eastern Turkey

The convergence between the Eurasian and Arabian plates has created a complicated structural setting in the Eastern Turkish high plateau (ETHP), particularly around the Karlıova Triple Junction (KTJ) where the Eurasian, Arabian, and Anatolian plates intersect. This region of interest includes the junction of the North Anatolian Shear Zone (NASZ) and the East Anatolian Shear Zone (EASZ), which forms the northern border of the westwardly extruding Anatolian Scholle and the western boundary of the ETHP, respectively. In this study, we focused on a poorly studied component of the KTJ, the Varto Fault Zone (VFZ), and the adjacent secondary structures, which have complex structural settings. Through integrated analyses of remote sensing and field observations, we identified a widely distributed transpressional zone where the Varto segment of the VFZ forms the most northern boundary. The other segments, namely, the Leylekdağ and Çayçatı segments, are oblique-reverse faults that are significantly defined by uplifted topography along their strikes. The measured 515 and 265 m of cumulative uplifts for Mt. Leylek and Mt. Dodan, respectively, yield a minimum uplift rate of 0.35 mm/a for the last 2.2 Ma. The multi-oriented secondary structures were mostly correlated with “the distributed strike-slip” and “the distributed transpressional” in analogue experiments. The misfits in strike of some of secondary faults between our observations and the experimental results were justified by about 20° to 25° clockwise restoration of all relevant structures that were palaeomagnetically measured to have happened since ~ 2.8 Ma ago. Our detected fault patterns and their true nature are well aligned as being part of a transpressional tectonic setting that supports previously suggested stationary triple junction models.

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.

Contrasting PT paths within the Barchi-Kol UHP terrain (Kokchetav Complex): Implications for subduction and exhumation of continental crust

The Barchi-Kol terrain is a classic locality of ultrahigh-pressure (UHP) metamorphism within the Kokchetav metamorphic belt. We provide a detailed and systematic characterization of four metasedimentary samples using dominant mineral assemblages, mineral inclusions in zircon and monazite, garnet zonation with respect to major and trace elements, and Zr-in-rutile and Ti-in-zircon temperatures. A typical diamond-bearing gneiss records peak conditions of 49 ± 4 kbar and 950–1000 °C. Near isothermal decompression of this rock resulted in the breakdown of phengite associated with a pervasive recrystallization of the rock. The same terrain also contains mica schists that experienced peak conditions close to those of the diamond-bearing rocks, but they were exhumed along a cooler path where phengite remained stable. In these rocks, major and trace element zoning in garnet has been completely equilibrated. A layered gneiss was metamorphosed at UHP conditions in the coesite field, but did not reach diamond-facies conditions (peak conditions: 30 kbar and 800–900 °C). In this sample, garnet records retrograde zonation in major elements and also retains prograde zoning in trace elements. A garnet-kyanite-micaschist that reached significantly lower pressures (24 ± 2 kbar, 710 ± 20 °C) contains garnet with major and trace element zoning. The diverse garnet zoning in samples that experienced different metamorphic conditions allows to establish that diffusional equilibration of rare earth element in garnet likely occurs at ~900–950 °C. Different metamorphic conditions in the four investigated samples are also documented in zircon trace element zonation and mineral inclusions in zircon and monazite. U-Pb geochronology of metamorphic zircon and monazite domains demonstrates that prograde (528–521 Ma), peak (528–522 Ma), and peak to retrograde metamorphism (503–532 Ma) occurred over a relatively short time interval that is indistinguishable from metamorphism of other UHP rocks within the Kokchetav metamorphic belt. Therefore, the assembly of rocks with contrasting P-T trajectories must have occurred in a single subduction-exhumation cycle, providing a snapshot of the thermal structure of a subducted continental margin prior to collision. The rocks were initially buried along a low geothermal gradient. At 20–25 kbar they underwent near isobaric heating of 200 °C, which was followed by continued burial along a low geothermal gradient. Such a step-wise geotherm is in good agreement with predictions from subduction zone thermal models.

Breaking Points: Mutiny in the Continental Army

The mutinies of the Continental Army during the American Revolution threatened both the integrity of the army and the viability of the Revolution itself. They were complex phenomena, stemming from numerous underlying physical and psychological causes. Having slowly developed over the course of the war, the problems confronting the Continental Army eventually brought it to the breaking point. No less than four major mutinies, involving soldiers or officers, occurred between 1780-1783. This essay focuses on the reasons for the mutinies and how the participants justified their actions. It also examines responses from General Washington and other senior officers, and what effects these actions had on the army. Finally, this essay addresses the question of why so few major mutinies occurred given the miserable state of the Continental Army.

The impact of Medicare, Medicaid and Schip Extension Act of 2007 (MMSEA) on the long term acute care hospitals

The Long Term Acute Care Hospitals (LTACH), which serve medically complex patients, have grown tremendously in recent years, by expanding the number of Medicare patient admissions and thus increasing Medicare expenditures (Stark 2004). In an attempt to mitigate the rapid growth of the LTACHs and reduce related Medicare expenditures, Congress enacted Section 114 of P.L. 110-173 (§114) of the Medicare, Medicaid and SCHIP Extension Act (MMSEA) in December 29, 2007 to regulate the LTCAHs industry. MMSEA increased the medical necessity reviews for Medicare admissions, imposed a moratorium on new LTCAHs, and allowed the Centers for Medicare and Medicaid Services (CMS) to recoup Medicare overpayments for unnecessary admissions. ^ This study examines whether MMSEA impacted LTACH admissions, operating margins and efficiency. These objectives were analyzed by comparing LTACH data for 2008 (post MMSEA) and data for 2006-2007 (pre-MMSEA). Secondary data were utilized from the American Hospital Association (AHA) database and the American Hospital Directory (AHD).^ This is a longitudinal retrospective study with a total sample of 55 LTACHs, selected from 396 LTACHs facilities that were fully operational during the study period of 2006-2008. The results of the research found no statistically significant change in total Medicare admissions; instead there was a small but not statistically significant reduction of 5% in Medicare admissions for 2008 in comparison to those for 2006. A statistically significant decrease in mean operating margins was confirmed between the years 2006 and 2008. The LTACHs' Technical Efficiency (TE), as computed by Data Envelopment Analysis (DEA), showed significant decrease in efficiency over the same period. Thirteen of the 55 LTACHs in the sample (24%) in 2006 were calculated as “efficient” utilizing the DEA analysis. This dropped to 13% (7/55) in 2008. Longitudinally, the decrease in efficiency using the DEA extension technique (Malmquist Index or MI) indicated a deterioration of 10% in efficiency over the same period. Interestingly, however, when the sample was stratified into high efficient versus low efficient subgroups (approximately 25% in each group), a comparison of the MIs suggested a significant improvement in Efficiency Change (EC) for the least efficient (MI 0.92022) and reduction in efficiency for the most efficient LTACHs (MI = 1.38761) over same period. While a reduction in efficiency for the most efficient is unexpected, it is not particularly surprising, since efficiency measure can vary over time. An improvement in efficiency, however, for the least efficient should be expected as those LTACHs begin to manage expenses (and controllable resources) more carefully to offset the payment/reimbursement pressures on their margins from MMSEA.^

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. ^

Dengue transmission risk maps of the continental United States

Dengue fever is a strictly human and non-human primate disease characterized by a high fever, thrombocytopenia, retro-orbital pain, and severe joint and muscle pain. Over 40% of the world population is at risk. Recent re-emergence of dengue outbreaks in Texas and Florida following the re-introduction of competent Aedes mosquito vectors in the United States have raised growing concerns about the potential for increased occurrences of dengue fever outbreaks throughout the southern United States. Current deficiencies in vector control, active surveillance and awareness among medical practitioners may contribute to a delay in recognizing and controlling a dengue virus outbreak. Previous studies have shown links between low-income census tracts, high population density, and dengue fever within the United States. Areas of low-income and high population density that correlate with the distribution of Aedes mosquitoes result in higher potential for outbreaks. In this retrospective ecologic study, nine maps were generated to model U.S. census tracts’ potential to sustain dengue virus transmission if the virus was introduced into the area. Variables in the model included presence of a competent vector in the county and census tract percent poverty and population density. Thirty states, 1,188 counties, and 34,705 census tracts were included in the analysis. Among counties with Aedes mosquito infestation, the census tracts were ranked high, medium, and low risk potential for sustained transmission of the virus. High risk census tracts were identified as areas having the vector, ≥20% poverty, and ≥500 persons per square mile. Census tracts with either ≥20% poverty or ≥500 persons per square mile and have the vector present are considered moderate risk. Census tracts that have the vector present but have <20% poverty and <500 persons per square mile are considered low risk. Furthermore, counties were characterized as moderate risk if 50% or more of the census tracts in that county were rated high or moderate risk, and high risk if 25% or greater were rated high risk. Extreme risk counties, which were primarily concentrated in Texas and Mississippi, were considered having 50% or greater of the census tracts ranked as high risk. Mapping of geographic areas with potential to sustain dengue virus transmission will support surveillance efforts and assist medical personnel in recognizing potential cases. ^

Age -period -cohort analysis: An extension of Cox's lifetable regression with time -dependent covariates

It is well known that an identification problem exists in the analysis of age-period-cohort data because of the relationship among the three factors (date of birth + age at death = date of death). There are numerous suggestions about how to analyze the data. No one solution has been satisfactory. The purpose of this study is to provide another analytic method by extending the Cox's lifetable regression model with time-dependent covariates. The new approach contains the following features: (1) It is based on the conditional maximum likelihood procedure using a proportional hazard function described by Cox (1972), treating the age factor as the underlying hazard to estimate the parameters for the cohort and period factors. (2) The model is flexible so that both the cohort and period factors can be treated as dummy or continuous variables, and the parameter estimations can be obtained for numerous combinations of variables as in a regression analysis. (3) The model is applicable even when the time period is unequally spaced.^ Two specific models are considered to illustrate the new approach and applied to the U.S. prostate cancer data. We find that there are significant differences between all cohorts and there is a significant period effect for both whites and nonwhites. The underlying hazard increases exponentially with age indicating that old people have much higher risk than young people. A log transformation of relative risk shows that the prostate cancer risk declined in recent cohorts for both models. However, prostate cancer risk declined 5 cohorts (25 years) earlier for whites than for nonwhites under the period factor model (0 0 0 1 1 1 1). These latter results are similar to the previous study by Holford (1983).^ The new approach offers a general method to analyze the age-period-cohort data without using any arbitrary constraint in the model. ^

Chemical analysis and argon geochronology from dive SAR_1 on Cornacya seamount of the Sardinia Channel

Sarcya 1 dive explored a previously unknown 12 My old submerged volcano, labelled Cornacya. A well developed fracturation is characterised by the following directions: N 170 to N-S, N 20 to N 40, N 90 to N 120, N 50 to N 70, which corresponds to the fracturation pattern of the Sardinian margin. The sampled lavas exhibit features of shoshonitic suites of intermediate composition and include amphibole-and mica-bearing lamprophyric xenoliths which are geochemically similar to Ti-poor lamproites. Mica compositions reflect chemical exchanges between the lamprophyre and its shoshonitic host rock suggesting their simultaneous emplacement. Nd compositions of the Cornacya K-rich suite indicate that continental crust was largely involved in the genesis of these rocks. The spatial association of the lamprophyre with the shoshonitic rocks is geochemically similar to K-rich and TiO2-poor igneous suites, emplaced in post-collisional settings. Among shoshonitic rocks, sample SAR 1-01 has been dated at 12.6±0.3 My using the 40Ar/39Ar method with a laser microprobe on single grains. The age of the Cornacya shoshonitic suite is similar to that of the Sisco lamprophyre from Corsica, which similarly is located on the western margin of the Tyrrhenian Sea. Thus, the Cornacya shoshonitic rocks and their lamprophyric xenolith and the Sisco lamprophyre could represent post-collisional suites emplaced during the lithospheric extension of the Corsica-Sardinia block, just after its rotation and before the Tyrrhenian sea opening. Drilling on the Sardinia margin (ODP Leg 107) shows that the upper levels of the present day margin (Hole 654) suffered tectonic subsidence before the lower part (Hole 652). The structure of this lower part is interpreted as the result of an eastward migration of the extension during Late Miocene and Early Pliocene times. Data of Cornacya volcano are in good agreement with this model and provide good chronological constraints for the beginning of the phenomenon.

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.

Elevation lines of modelled ice sheet extension during last glacial maximum

A numerical ice-sheet model was used to reconstruct the Late Weichselian glaciation of the Eurasian High Arctic, between Franz Josef Land and Severnaya Zemlya. An ice sheet was developed over the entire Eurasian High Arctic so that ice flow from the central Barents and Kara seas toward the northern Russian Arctic could be accounted for. An inverse approach to modeling was utilized, where ice-sheet results were forced to be compatible with geological information indicating ice-free conditions over the Taymyr Peninsula during the Late Weichselian. The model indicates complete glaciation of the Barents and Kara seas and predicts a "maximum-sized" ice sheet for the Late Weichselian Russian High Arctic. In this scenario, full-glacial conditions are characterized by a 1500-m-thick ice mass over the Barents Sea, from which ice flowed to the north and west within several bathymetric troughs as large ice streams. In contrast to this reconstruction, a "minimum" model of glaciation involves restricted glaciation in the Kara Sea, where the ice thickness is only 300 m in the south and which is free of ice in the north across Severnaya Zemlya. Our maximum reconstruction is compatible with geological information that indicates complete glaciation of the Barents Sea. However, geological data from Severnaya Zemlya suggest our minimum model is more relevant further east. This, in turn, implies a strong paleoclimatic gradient to colder and drier conditions eastward across the Eurasian Arctic during the Late Weichselian.