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Nickel phosphides are of particular interest because they are highly active and stable catalysts for petroleum/biorefinery and hydrogen production. Despite their significant catalytic potential, synthesizing various phase-pure nickel phosphide nanoparticles of uniform size remains a challenge. In this work, we develop a robust trioctylphosphine (TOP)-mediated route to make highly uniform phase-pure Ni12P5, Ni2P, and Ni5P4 nanoparticles. The synthetic route forms amorphous Ni70P30 nanoparticle intermediates. The reactions can be stopped at the amorphous stage when amorphous particles are desired. The amount of P incorporation can be controlled by varying the ratio of TOP to Ni(II). The mechanism for composition control involves the competition of the kinetics of two processes: the addition of the reduced Ni and the incorporation of P into Ni. Uniform Ni70P30 amorphous nanoparticles can be generated at a high TOP-to-Ni(II) ratio, where the P incorporation kinetics is made to dominate. Ni70P30 can later be transformed into phase-pure Ni12P5, Ni2P, and Ni5P4 nanocrystals of uniform size. The transformation can be controlled precisely by modulating the temperature. A UV-vis study coupled with theoretical modeling reveals Ni(0)-TOPx complexes along the synthetic path. This approach may be expanded to create other metal compounds, potentially enabling the synthesis of uniform nanoparticles of a greater variety.

Carbon dioxide and methane emissions are the two primary anthropogenic climate-forcing agents and an important source of uncertainty in the global carbon budget. Uncertainties are further magnified when emissions occur at fine spatial scales (

Abstract: Chemical and biological composition of surface materials and physical structure and arrangement of those materials determine the intrinsic reflectance of Earth's land surface. The apparent reflectance—as measured by a spaceborne or airborne sensor that has been corrected for atmospheric attenuation—depends also on topography, surface roughness, and the atmosphere. Especially in Earth's mountains, estimating properties of scientific interest from remotely sensed data requires compensation for topography. Doing so requires information from digital elevation models (DEMs). Available DEMs with global coverage are derived from spaceborne interferometric radar and stereo‐photogrammetry at ∼30 m spatial resolution. Locally or regionally, lidar altimetry, interferometric radar, or stereo‐photogrammetry produces DEMs with finer resolutions. Characterization of their quality typically expresses the root‐mean‐square (RMS) error of the elevation, but the accuracy of remotely sensed retrievals is sensitive to uncertainties in topographic properties that affect incoming and reflected radiation and that are inadequately represented by the RMS error of the elevation. The most essential variables are the cosine of the local solar illumination angle on a slope, the shadows cast by neighboring terrain, and the view factor, the fraction of the overlying hemisphere open to the sky. Comparison of global DEMs with locally available fine‐scale DEMs shows that calculations with the global products consistently underestimate the cosine of the solar angle and underrepresent shadows. Analyzing imagery of Earth's mountains from current and future spaceborne missions requires addressing the uncertainty introduced by errors in DEMs on algorithms that analyze remotely sensed data to produce information about Earth's surface.

With the scaling of lateral dimensions in advanced transistors, an increased gate capacitance is desirable both to retain the control of the gate electrode over the channel and to reduce the operating voltage1. This led to a fundamental change in the gate stack in 2008, the incorporation of high-dielectric-constant HfO2 (ref. 2), which remains the material of choice to date. Here we report HfO2-ZrO2 superlattice heterostructures as a gate stack, stabilized with mixed ferroelectric-antiferroelectric order, directly integrated onto Si transistors, and scaled down to approximately 20 ångströms, the same gate oxide thickness required for high-performance transistors. The overall equivalent oxide thickness in metal-oxide-semiconductor capacitors is equivalent to an effective SiO2 thickness of approximately 6.5 ångströms. Such a low effective oxide thickness and the resulting large capacitance cannot be achieved in conventional HfO2-based high-dielectric-constant gate stacks without scavenging the interfacial SiO2, which has adverse effects on the electron transport and gate leakage current3. Accordingly, our gate stacks, which do not require such scavenging, provide substantially lower leakage current and no mobility degradation. This work demonstrates that ultrathin ferroic HfO2-ZrO2 multilayers, stabilized with competing ferroelectric-antiferroelectric order in the two-nanometre-thickness regime, provide a path towards advanced gate oxide stacks in electronic devices beyond conventional HfO2-based high-dielectric-constant materials.

Droughts in a warming climate have become more common and more extreme, making understanding forest responses to water stress increasingly pressing. Analysis of water stress in trees has long focused on water potential in xylem and leaves, which influences stomatal closure and water flow through the soil-plant-atmosphere continuum. At the same time, changes of vegetation water content (VWC) are linked to a range of tree responses, including fluxes of water and carbon, mortality, flammability, and more. Unlike water potential, which requires demanding in situ measurements, VWC can be retrieved from remote sensing measurements, particularly at microwave frequencies using radar and radiometry. Here, we highlight key frontiers through which VWC has the potential to significantly increase our understanding of forest responses to water stress. To validate remote sensing observations of VWC at landscape scale and to better relate them to data assimilation model parameters, we introduce an ecosystem-scale analog of the pressure-volume curve, the non-linear relationship between average leaf or branch water potential and water content commonly used in plant hydraulics. The sources of variability in these ecosystem-scale pressure-volume curves and their relationship to forest response to water stress are discussed. We further show to what extent diel, seasonal, and decadal dynamics of VWC reflect variations in different processes relating the tree response to water stress. VWC can also be used for inferring belowground conditions-which are difficult to impossible to observe directly. Lastly, we discuss how a dedicated geostationary spaceborne observational system for VWC, when combined with existing datasets, can capture diel and seasonal water dynamics to advance the science and applications of global forest vulnerability to future droughts.

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.

The 2017–2027 National Academies' Decadal Survey, Thriving on Our Changing Planet, recommended Surface Biology and Geology (SBG) as a “Designated Targeted Observable” (DO). The SBG DO is based on the need for capabilities to acquire global, high spatial resolution, visible to shortwave infrared (VSWIR; 380–2500 nm; ~30 m pixel resolution) hyperspectral (imaging spectroscopy) and multispectral midwave and thermal infrared (MWIR: 3–5 μm; TIR: 8–12 μm; ~60 m pixel resolution) measurements with sub-monthly temporal revisits over terrestrial, freshwater, and coastal marine habitats. To address the various mission design needs, an SBG Algorithms Working Group of multidisciplinary researchers has been formed to review and evaluate the algorithms applicable to the SBG DO across a wide range of Earth science disciplines, including terrestrial and aquatic ecology, atmospheric science, geology, and hydrology. Here, we summarize current state-of-the-practice VSWIR and TIR algorithms that use airborne or orbital spectral imaging observations to address the SBG DO priorities identified by the Decadal Survey: (i) terrestrial vegetation physiology, functional traits, and health; (ii) inland and coastal aquatic ecosystems physiology, functional traits, and health; (iii) snow and ice accumulation, melting, and albedo; (iv) active surface composition (eruptions, landslides, evolving landscapes, hazard risks); (v) effects of changing land use on surface energy, water, momentum, and carbon fluxes; and (vi) managing agriculture, natural habitats, water use/quality, and urban development. We review existing algorithms in the following categories: snow/ice, aquatic environments, geology, and terrestrial vegetation, and summarize the community-state-of-practice in each category. This effort synthesizes the findings of more than 130 scientists.

Abstract. The large uncertainty in the mineral dust direct radiative effect (DRE) hinders projections of future climate change due toanthropogenic activity. Resolving modeled dust mineral speciation allows for spatially and temporally varying refractive indices consistent with dust aerosol composition. Here, for the first time, we quantify the range in dustDRE at the top of the atmosphere (TOA) due to current uncertainties in thesurface soil mineralogical content using a dust mineral-resolving climatemodel. We propagate observed uncertainties in soil mineral abundances fromtwo soil mineralogy atlases along with the optical properties of eachmineral into the DRE and compare the resultant range with other sources ofuncertainty across six climate models. The shortwave DRE responds region-specifically to the dust burden depending on the mineral speciationand underlying shortwave surface albedo: positively when the regionally averaged annual surface albedo is larger than 0.28 and negativelyotherwise. Among all minerals examined, the shortwave TOA DRE and singlescattering albedo at the 0.44–0.63 µm band are most sensitive to thefractional contribution of iron oxides to the total dust composition. Theglobal net (shortwave plus longwave) TOA DRE is estimated to be within −0.23to +0.35 W m−2. Approximately 97 % of this range relates touncertainty in the soil abundance of iron oxides. Representing iron oxide with solely hematite optical properties leads to an overestimation ofshortwave DRE by +0.10 W m−2 at the TOA, as goethite is not asabsorbing as hematite in the shortwave spectrum range. Our study highlightsthe importance of iron oxides to the shortwave DRE: they have adisproportionally large impact on climate considering their smallatmospheric mineral mass fractional burden (∼2 %). Animproved description of iron oxides, such as those planned in the EarthSurface Mineral Dust Source Investigation (EMIT), is thus essential for moreaccurate estimates of the dust DRE.

Southern Ocean ecosystems are under pressure from resource exploitation and climate change1,2. Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40°S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.

Accurate and timely detection, quantification, and attribution of methane emissions from Underground Gas Storage (UGS) facilities is essential for improving confidence in greenhouse gas inventories, enabling emission mitigation by facility operators, and supporting efforts to assess facility integrity and safety. We conducted multiple airborne surveys of the 12 active UGS facilities in California between January 2016 and November 2017 using advanced remote sensing and in situ observations of near-surface atmospheric methane (CH4). These measurements where combined with wind data to derive spatially and temporally resolved methane emission estimates for California UGS facilities and key components with spatial resolutions as small as 1-3 m and revisit intervals ranging from minutes to months. The study spanned normal operations, malfunctions, and maintenance activity from multiple facilities including the active phase of the Aliso Canyon blowout incident in 2016 and subsequent return to injection operations in summer 2017. We estimate that the net annual methane emissions from the UGS sector in California averaged between 11.0 3.8 GgCH4 yr-1 (remote sensing) and 12.3 3.8 GgCH4 yr-1 (in situ). Net annual methane emissions for the 7 facilities that reported emissions in 2016 were estimated between 9.0 3.2 GgCH4 yr-1 (remote sensing) and 9.5 3.2 GgCH4 yr-1 (in situ), in both cases around 5 times higher than reported. The majority of methane emissions from UGS facilities in this study are likely dominated by anomalous activity: higher than expected compressor loss and leaking bypass isolation valves. Significant variability was observed at different time-scales: daily compressor duty-cycles and infrequent but large emissions from compressor station blow-downs. This observed variability made comparison of remote sensing and in situ observations challenging given measurements were derived largely at different times, however, improved agreement occurred when comparing simultaneous measurements. Temporal variability in emissions remains one of the most challenging aspects of UGS emissions quantification, underscoring the need for more systematic and persistent methane monitoring.

Southern Ocean ecosystems are under pressure from resource exploitation and climate change1,2. Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40°S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.

The Retrospective Analysis of Antarctic Tracking Data (RAATD) is a Scientific Committee for Antarctic Research project led jointly by the Expert Groups on Birds and Marine Mammals and Antarctic Biodiversity Informatics, and endorsed by the Commission for the Conservation of Antarctic Marine Living Resources. RAATD consolidated tracking data for multiple species of Antarctic meso- and top-predators to identify Areas of Ecological Significance. These datasets and accompanying syntheses provide a greater understanding of fundamental ecosystem processes in the Southern Ocean, support modelling of predator distributions under future climate scenarios and create inputs that can be incorporated into decision making processes by management authorities. In this data paper, we present the compiled tracking data from research groups that have worked in the Antarctic since the 1990s. The data are publicly available through biodiversity.aq and the Ocean Biogeographic Information System. The archive includes tracking data from over 70 contributors across 12 national Antarctic programs, and includes data from 17 predator species, 4060 individual animals, and over 2.9 million observed locations.

The Retrospective Analysis of Antarctic Tracking Data (RAATD) is a Scientific Committee for Antarctic Research project led jointly by the Expert Groups on Birds and Marine Mammals and Antarctic Biodiversity Informatics, and endorsed by the Commission for the Conservation of Antarctic Marine Living Resources. RAATD consolidated tracking data for multiple species of Antarctic meso- and top-predators to identify Areas of Ecological Significance. These datasets and accompanying syntheses provide a greater understanding of fundamental ecosystem processes in the Southern Ocean, support modelling of predator distributions under future climate scenarios and create inputs that can be incorporated into decision making processes by management authorities. In this data paper, we present the compiled tracking data from research groups that have worked in the Antarctic since the 1990s. The data are publicly available through biodiversity.aq and the Ocean Biogeographic Information System. The archive includes tracking data from over 70 contributors across 12 national Antarctic programs, and includes data from 17 predator species, 4060 individual animals, and over 2.9 million observed locations.

The Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission will carry into space the Ocean Color Instrument (OCI), a spectrometer measuring at 5nm spectral resolution in the ultraviolet (UV) to near infrared (NIR) with additional spectral bands in the shortwave infrared (SWIR), and two multi-angle polarimeters that will overlap the OCI spectral range and spatial coverage, i. e., the Spectrometer for Planetary Exploration (SPEXone) and the Hyper-Angular Rainbow Polarimeter (HARP2). These instruments, especially when used in synergy, have great potential for improving estimates of water reflectance in the post Earth Observing System (EOS) era. Extending the top-of-atmosphere (TOA) observations to the UV, where aerosol absorption is effective, adding spectral bands in the SWIR, where even the most turbid waters are black and sensitivity to the aerosol coarse mode is higher than at shorter wavelengths, and measuring in the oxygen A-band to estimate aerosol altitude will enable greater accuracy in atmospheric correction for ocean color science. The multi-angular and polarized measurements, sensitive to aerosol properties (e.g., size distribution, index of refraction), can further help to identify or constrain the aerosol model, or to retrieve directly water reflectance. Algorithms that exploit the new capabilities are presented, and their ability to improve accuracy is discussed. They embrace a modern, adapted heritage two-step algorithm and alternative schemes (deterministic, statistical) that aim at inverting the TOA signal in a single step. These schemes, by the nature of their construction, their robustness, their generalization properties, and their ability to associate uncertainties, are expected to become the new standard in the future. A strategy for atmospheric correction is presented that ensures continuity and consistency with past and present ocean-color missions while enabling full exploitation of the new dimensions and possibilities. Despite the major improvements anticipated with the PACE instruments, gaps/issues remain to be filled/tackled. They include dealing properly with whitecaps, taking into account Earth-curvature effects, correcting for adjacency effects, accounting for the coupling between scattering and absorption, modeling accurately water reflectance, and acquiring a sufficiently representative dataset of water reflectance in the UV to SWIR. Dedicated efforts, experimental and theoretical, are in order to gather the necessary information and rectify inadequacies. Ideas and solutions are put forward to address the unresolved issues. Thanks to its design and characteristics, the PACE mission will mark the beginning of a new era of unprecedented accuracy in ocean-color radiometry from space.

PurposeNitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the mechanisms by which NM induces corneal damage by examining the impact of NM exposure on the morphology and lipidome of the cornea.MethodsIntact ex vivo rabbit eyes were placed in serum-free DMEM organ culture. NM (0, 1, 2.5, 5 or 10 mg/ml) was applied to the central cornea for 5, 10 or 15 min using a 5 mm filter disk and subsequently rinsed with DMEM. Corneas were then cultured for 3, 24, or 48 h before being fixed for morphological analysis or for 24 h before being snap frozen for lipidomic analysis.ResultsNo morphological changes were detected 3 h after NM exposure. Twenty-four h after exposure, 1 mg/ml NM caused erosion of the corneal epithelium, but no damage to the underlying stroma. Damage caused by 2.5 mg/ml NM extended almost two thirds through the corneal stroma, while 5 mg/ml completely penetrated the corneal stroma. An altered lipid profile occurred 24 h after corneas were exposed to NM. Specific sphingomyelins, ceramides, and diacylglycerols were increased up to 9-, 60- and 10-fold, respectively.ConclusionsNM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramide pathway may contribute to the damaging effects of NM exposure.

Abstract. At local scales, emissions of methane and carbon dioxide are highly uncertain. Localized sources of both trace gases can create strong local gradients in its columnar abundance, which can be discerned using absorption spectroscopy at high spatial resolution. In a previous study, more than 250 methane plumes were observed in the San Juan Basin near Four Corners during April 2015 using the next-generation Airborne Visible/Infrared Imaging Spectrometer (AVIRIS-NG) and a linearized matched filter. For the first time, we apply the iterative maximum a posteriori differential optical absorption spectroscopy (IMAP-DOAS) method to AVIRIS-NG data and generate gas concentration maps for methane, carbon dioxide, and water vapor plumes. This demonstrates a comprehensive greenhouse gas monitoring capability that targets methane and carbon dioxide, the two dominant anthropogenic climate-forcing agents. Water vapor results indicate the ability of these retrievals to distinguish between methane and water vapor despite spectral interference in the shortwave infrared. We focus on selected cases from anthropogenic and natural sources, including emissions from mine ventilation shafts, a gas processing plant, tank, pipeline leak, and natural seep. In addition, carbon dioxide emissions were mapped from the flue-gas stacks of two coal-fired power plants and a water vapor plume was observed from the combined sources of cooling towers and cooling ponds. Observed plumes were consistent with known and suspected emission sources verified by the true color AVIRIS-NG scenes and higher-resolution Google Earth imagery. Real-time detection and geolocation of methane plumes by AVIRIS-NG provided unambiguous identification of individual emission source locations and communication to a ground team for rapid follow-up. This permitted verification of a number of methane emission sources using a thermal camera, including a tank and buried natural gas pipeline.

Characterizing how physical and psychological symptoms interact in heart transplant recipients may lead to advances in therapeutic options. This study examined associations between pain and major depression.MethodA cross-sectional study was conducted with adult heart transplant recipients. Pain was measured with the bodily pain domain of the Short Form-36 Health Survey and psychological distress with the Kessler Psychological Distress Scale (K-10). The Mini International Neuropsychiatric Interview, version 6.0, was used to identify participants meeting the criteria for major depression. Hierarchical linear regression was used to determine if there was an association between pain and major depression, controlling for pharmacological treatment of depression, severity of psychological distress, and clinical characteristics including immunosuppression medication which may induce pain as a side effect.ResultsAverage pain score of the 48 heart transplant recipients was 43 ( SD ± 10, range 0-100, lower scores indicate worse pain), with moderate pain reported by 39% ( n = 19). Major depression was associated with worse pain ( R2 change = 36%, β = -16, 95% confidence interval [CI] = [-30, -4], p = .012). Pharmacological treatment for depression was associated with better pain scores ( R2 change = 1.5%, β = 13, 95% CI [4, 23], p = .006).ConclusionsHeart transplant recipients with major depression had worse pain after controlling for pharmacological treatment of depression, severity of psychological distress, and clinical characteristics. Thus, it is imperative that clinicians devising a treatment regimen for pain in heart transplant recipients take into account co-occurring depression and vice versa.

Abstract. At local scales, emissions of methane and carbon dioxide are highly uncertain. Localized sources of both trace gases can create strong local gradients in its columnar abundance, which can be discerned using absorption spectroscopy at high spatial resolution. In a previous study, more than 250 methane plumes were observed in the San Juan Basin near Four Corners during April 2015 using the next-generation Airborne Visible/Infrared Imaging Spectrometer (AVIRIS-NG) and a linearized matched filter. For the first time, we apply the iterative maximum a posteriori differential optical absorption spectroscopy (IMAP-DOAS) method to AVIRIS-NG data and generate gas concentration maps for methane, carbon dioxide, and water vapor plumes. This demonstrates a comprehensive greenhouse gas monitoring capability that targets methane and carbon dioxide, the two dominant anthropogenic climate-forcing agents. Water vapor results indicate the ability of these retrievals to distinguish between methane and water vapor despite spectral interference in the shortwave infrared. We focus on selected cases from anthropogenic and natural sources, including emissions from mine ventilation shafts, a gas processing plant, tank, pipeline leak, and natural seep. In addition, carbon dioxide emissions were mapped from the flue-gas stacks of two coal-fired power plants and a water vapor plume was observed from the combined sources of cooling towers and cooling ponds. Observed plumes were consistent with known and suspected emission sources verified by the true color AVIRIS-NG scenes and higher-resolution Google Earth imagery. Real-time detection and geolocation of methane plumes by AVIRIS-NG provided unambiguous identification of individual emission source locations and communication to a ground team for rapid follow-up. This permitted verification of a number of methane emission sources using a thermal camera, including a tank and buried natural gas pipeline.

Characterizing how physical and psychological symptoms interact in heart transplant recipients may lead to advances in therapeutic options. This study examined associations between pain and major depression.MethodA cross-sectional study was conducted with adult heart transplant recipients. Pain was measured with the bodily pain domain of the Short Form-36 Health Survey and psychological distress with the Kessler Psychological Distress Scale (K-10). The Mini International Neuropsychiatric Interview, version 6.0, was used to identify participants meeting the criteria for major depression. Hierarchical linear regression was used to determine if there was an association between pain and major depression, controlling for pharmacological treatment of depression, severity of psychological distress, and clinical characteristics including immunosuppression medication which may induce pain as a side effect.ResultsAverage pain score of the 48 heart transplant recipients was 43 ( SD ± 10, range 0-100, lower scores indicate worse pain), with moderate pain reported by 39% ( n = 19). Major depression was associated with worse pain ( R2 change = 36%, β = -16, 95% confidence interval [CI] = [-30, -4], p = .012). Pharmacological treatment for depression was associated with better pain scores ( R2 change = 1.5%, β = 13, 95% CI [4, 23], p = .006).ConclusionsHeart transplant recipients with major depression had worse pain after controlling for pharmacological treatment of depression, severity of psychological distress, and clinical characteristics. Thus, it is imperative that clinicians devising a treatment regimen for pain in heart transplant recipients take into account co-occurring depression and vice versa.

PurposeThe aim of this study was to assess the validity and reliability of psychological screening tools in outpatient heart transplant recipients.MethodsForty-eight heart transplant recipients completed the Patient Health Questionnaire 9-item scale (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), Kessler Psychological Distress 10-item Scale (K-10) and Medical Outcomes Short Form 36-item Health Survey. A structured psychological interview (Mini International Neuropsychiatric Interview Version 6) was conducted after completion of the questionnaires. Internal consistency, criterion validity and construct validity of the PHQ-9, GAD-7 and K-10 were evaluated.ResultsInternal consistency supported the reliability of the screening tools. The optimal cut-off on the PHQ-9 for depression was 10 (sensitivity=0.86; specificity=0.93). A score of 6 on the GAD-7 maximized sensitivity (0.75) and specificity (0.89) for anxiety. A score of 17 on the K-10 was the optimal cut-off for diagnosis of either anxiety or depression (sensitivity=0.83; specificity=0.84). Increasing scores on the screening tools were associated with lower health-related quality of life.ConclusionPsychometric analyses support the reliability and validity of the PHQ-9, GAD-7 and K-10 as screening tools for detection of anxiety and depression in heart transplant recipients.

PurposeThe aim of this study was to assess the validity and reliability of psychological screening tools in outpatient heart transplant recipients.MethodsForty-eight heart transplant recipients completed the Patient Health Questionnaire 9-item scale (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), Kessler Psychological Distress 10-item Scale (K-10) and Medical Outcomes Short Form 36-item Health Survey. A structured psychological interview (Mini International Neuropsychiatric Interview Version 6) was conducted after completion of the questionnaires. Internal consistency, criterion validity and construct validity of the PHQ-9, GAD-7 and K-10 were evaluated.ResultsInternal consistency supported the reliability of the screening tools. The optimal cut-off on the PHQ-9 for depression was 10 (sensitivity=0.86; specificity=0.93). A score of 6 on the GAD-7 maximized sensitivity (0.75) and specificity (0.89) for anxiety. A score of 17 on the K-10 was the optimal cut-off for diagnosis of either anxiety or depression (sensitivity=0.83; specificity=0.84). Increasing scores on the screening tools were associated with lower health-related quality of life.ConclusionPsychometric analyses support the reliability and validity of the PHQ-9, GAD-7 and K-10 as screening tools for detection of anxiety and depression in heart transplant recipients.

Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis.

Aldehyde dehydrogenase 1A1 (ALDH1A1) and ALDH3A1 are corneal crystallins. They protect inner ocular tissues from ultraviolet radiation (UVR)-induced oxidative damage through catalytic and non-catalytic mechanisms. Additionally, ALDH3A1 has been postulated to play a regulatory role in the corneal epithelium based on several studies that report an inverse association between ALDH3A1 expression and corneal cell proliferation. The underlying molecular mechanisms and the physiological significance of such association remain poorly understood. In the current study, we established Tet-On human corneal epithelial cell (hTCEpi) lines, which express tetracycline-inducible wild-type (wt) or catalytically-inactive (mu) ALDH3A1. Utilizing this cellular model system, we confirmed that human ALDH3A1 decreases corneal cell proliferation; importantly, this effect appears to be partially mediated by its enzymatic activity. Mechanistically, wt-ALDH3A1, but not mu-ALDH3A1, promotes sequestering of tumor suppressor p53 in the nucleus. In the mouse cornea, however, augmented cell proliferation is noted only in Aldh1a1(-/-)/3a1(-/-) double knockout (DKO) mice, indicating in vivo the anti-proliferation effect of ALDH3A1 can be rescued by the presence of ALDH1A1. Interestingly, the hyper-proliferative epithelium of the DKO corneas display nearly complete loss of p53 expression, implying that p53 may be involved in ALDH3A1/1A1-mediated effect. In hTCEpi cells grown in high calcium concentration, mRNA levels of a panel of corneal differentiation markers were altered by ALDH3A1 expression and modulated by its enzyme activity. In conclusion, we show for the first time that: (i) ALDH3A1 decreases corneal epithelial proliferation through both non-enzymatic and enzymatic properties; (ii) ALDH1A1 contributes to the regulation of corneal cellular proliferation in vivo; and (iii) ALDH3A1 modulates corneal epithelial differentiation. Collectively, our studies indicate a functional role of ALDH3A1 in the maintenance of corneal epithelial homeostasis by simultaneously modulating proliferation and differentiation through both enzymatic and non-enzymatic mechanisms.

Aldehyde dehydrogenase 1A1 (ALDH1A1) and ALDH3A1 are corneal crystallins. They protect inner ocular tissues from ultraviolet radiation (UVR)-induced oxidative damage through catalytic and non-catalytic mechanisms. Additionally, ALDH3A1 has been postulated to play a regulatory role in the corneal epithelium based on several studies that report an inverse association between ALDH3A1 expression and corneal cell proliferation. The underlying molecular mechanisms and the physiological significance of such association remain poorly understood. In the current study, we established Tet-On human corneal epithelial cell (hTCEpi) lines, which express tetracycline-inducible wild-type (wt) or catalytically-inactive (mu) ALDH3A1. Utilizing this cellular model system, we confirmed that human ALDH3A1 decreases corneal cell proliferation; importantly, this effect appears to be partially mediated by its enzymatic activity. Mechanistically, wt-ALDH3A1, but not mu-ALDH3A1, promotes sequestering of tumor suppressor p53 in the nucleus. In the mouse cornea, however, augmented cell proliferation is noted only in Aldh1a1(-/-)/3a1(-/-) double knockout (DKO) mice, indicating in vivo the anti-proliferation effect of ALDH3A1 can be rescued by the presence of ALDH1A1. Interestingly, the hyper-proliferative epithelium of the DKO corneas display nearly complete loss of p53 expression, implying that p53 may be involved in ALDH3A1/1A1-mediated effect. In hTCEpi cells grown in high calcium concentration, mRNA levels of a panel of corneal differentiation markers were altered by ALDH3A1 expression and modulated by its enzyme activity. In conclusion, we show for the first time that: (i) ALDH3A1 decreases corneal epithelial proliferation through both non-enzymatic and enzymatic properties; (ii) ALDH1A1 contributes to the regulation of corneal cellular proliferation in vivo; and (iii) ALDH3A1 modulates corneal epithelial differentiation. Collectively, our studies indicate a functional role of ALDH3A1 in the maintenance of corneal epithelial homeostasis by simultaneously modulating proliferation and differentiation through both enzymatic and non-enzymatic mechanisms.

ObjectiveFor intracortical brain-machine interfaces (BMIs), action potential voltage waveforms are often sorted to separate out individual neurons. If these neurons contain independent tuning information, this process could increase BMI performance. However, the sorting of action potentials ('spikes') requires high sampling rates and is computationally expensive. To explicitly define the difference between spike sorting and alternative methods, we quantified BMI decoder performance when using threshold-crossing events versus sorted action potentials.ApproachWe used data sets from 58 experimental sessions from two rhesus macaques implanted with Utah arrays. Data were recorded while the animals performed a center-out reaching task with seven different angles. For spike sorting, neural signals were sorted into individual units by using a mixture of Gaussians to cluster the first four principal components of the waveforms. For thresholding events, spikes that simply crossed a set threshold were retained. We decoded the data offline using both a Naïve Bayes classifier for reaching direction and a linear regression to evaluate hand position.Main resultsWe found the highest performance for thresholding when placing a threshold between -3 and -4.5 × Vrms. Spike sorted data outperformed thresholded data for one animal but not the other. The mean Naïve Bayes classification accuracy for sorted data was 88.5% and changed by 5% on average when data were thresholded. The mean correlation coefficient for sorted data was 0.92, and changed by 0.015 on average when thresholded.SignificanceFor prosthetics applications, these results imply that when thresholding is used instead of spike sorting, only a small amount of performance may be lost. The utilization of threshold-crossing events may significantly extend the lifetime of a device because these events are often still detectable once single neurons are no longer isolated.

Cyanide causes toxic effects by inhibiting cytochrome c oxidase, resulting in cellular hypoxia and cytotoxic anoxia, and can eventually lead to death. Cyanide exposure can be verified by direct analysis of cyanide concentrations or analyzing its metabolites, including thiocyanate (SCN(-)) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA) in blood. To determine the behavior of these markers following cyanide exposure, a toxicokinetics study was performed in three animal models: (i) rats (250-300 g), (ii) rabbits (3.5-4.2 kg) and (iii) swine (47-54 kg). Cyanide reached a maximum in blood and declined rapidly in each animal model as it was absorbed, distributed, metabolized and eliminated. Thiocyanate concentrations rose more slowly as cyanide was enzymatically converted to SCN(-). Concentrations of ATCA did not rise significantly above the baseline in the rat model, but rose quickly in rabbits (up to a 40-fold increase) and swine (up to a 3-fold increase) and then fell rapidly, generally following the relative behavior of cyanide. Rats were administered cyanide subcutaneously and the apparent half-life (t1/2) was determined to be 1,510 min. Rabbits were administered cyanide intravenously and the t1/2 was determined to be 177 min. Swine were administered cyanide intravenously and the t1/2 was determined to be 26.9 min. The SCN(-) t1/2 in rats was 3,010 min, but was not calculated in rabbits and swine because SCN(-) concentrations did not reach a maximum. The t1/2 of ATCA was 40.7 and 13.9 min in rabbits and swine, respectively, while it could not be determined in rats with confidence. The current study suggests that cyanide exposure may be verified shortly after exposure by determining significantly elevated cyanide and SCN(-) in each animal model and ATCA may be used when the ATCA detoxification pathway is significant.

Cyanide causes toxic effects by inhibiting cytochrome c oxidase, resulting in cellular hypoxia and cytotoxic anoxia, and can eventually lead to death. Cyanide exposure can be verified by direct analysis of cyanide concentrations or analyzing its metabolites, including thiocyanate (SCN(-)) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA) in blood. To determine the behavior of these markers following cyanide exposure, a toxicokinetics study was performed in three animal models: (i) rats (250-300 g), (ii) rabbits (3.5-4.2 kg) and (iii) swine (47-54 kg). Cyanide reached a maximum in blood and declined rapidly in each animal model as it was absorbed, distributed, metabolized and eliminated. Thiocyanate concentrations rose more slowly as cyanide was enzymatically converted to SCN(-). Concentrations of ATCA did not rise significantly above the baseline in the rat model, but rose quickly in rabbits (up to a 40-fold increase) and swine (up to a 3-fold increase) and then fell rapidly, generally following the relative behavior of cyanide. Rats were administered cyanide subcutaneously and the apparent half-life (t1/2) was determined to be 1,510 min. Rabbits were administered cyanide intravenously and the t1/2 was determined to be 177 min. Swine were administered cyanide intravenously and the t1/2 was determined to be 26.9 min. The SCN(-) t1/2 in rats was 3,010 min, but was not calculated in rabbits and swine because SCN(-) concentrations did not reach a maximum. The t1/2 of ATCA was 40.7 and 13.9 min in rabbits and swine, respectively, while it could not be determined in rats with confidence. The current study suggests that cyanide exposure may be verified shortly after exposure by determining significantly elevated cyanide and SCN(-) in each animal model and ATCA may be used when the ATCA detoxification pathway is significant.

The aims of this study were to describe the changes in bone turnover markers (BTMs) in response to lasofoxifene therapy; to describe the changes in BTMs in the individual; and to examine the relationships between BTM levels on treatment and treatment outcomes. Women (n=1126) aged 59-80years with femoral neck or spine bone mineral density T-scores ≤-2.5 were randomized to lasofoxifene 0.25mg/d, 0.5mg/d, or placebo for 5years. We measured serum C-telopeptide of type I collagen (CTX) and serum procollagen I N-propeptide (PINP), osteocalcin, and bone alkaline phosphatase (ALP) at baseline and at 1, 3, 6, 12, 24, and 36months. Lasofoxifene therapy resulted in a decrease in the concentrations of bone resorption and bone formation markers compared with placebo; the decrease was maximal between 6 and 24months. The effect of lasofoxifene 0.5mg/d was similar to that of lasofoxifene 0.25mg/d. The decrease in bone ALP was less than the decreases in CTX, osteocalcin, and PINP. Lasofoxifene therapy 0.5mg/d resulted in BTM-defined response rates for CTX (decrease in concentration from baseline >60%), PINP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36months of lasofoxifene 0.5mg/d) and was not as specific (15% of placebo group responded). Bone density change was weakly inversely correlated with change in the concentrations of BTMs. BTMs may prove useful in the monitoring of the response to lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.

The aims of this study were to describe the changes in bone turnover markers (BTMs) in response to lasofoxifene therapy; to describe the changes in BTMs in the individual; and to examine the relationships between BTM levels on treatment and treatment outcomes. Women (n=1126) aged 59-80years with femoral neck or spine bone mineral density T-scores ≤-2.5 were randomized to lasofoxifene 0.25mg/d, 0.5mg/d, or placebo for 5years. We measured serum C-telopeptide of type I collagen (CTX) and serum procollagen I N-propeptide (PINP), osteocalcin, and bone alkaline phosphatase (ALP) at baseline and at 1, 3, 6, 12, 24, and 36months. Lasofoxifene therapy resulted in a decrease in the concentrations of bone resorption and bone formation markers compared with placebo; the decrease was maximal between 6 and 24months. The effect of lasofoxifene 0.5mg/d was similar to that of lasofoxifene 0.25mg/d. The decrease in bone ALP was less than the decreases in CTX, osteocalcin, and PINP. Lasofoxifene therapy 0.5mg/d resulted in BTM-defined response rates for CTX (decrease in concentration from baseline >60%), PINP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36months of lasofoxifene 0.5mg/d) and was not as specific (15% of placebo group responded). Bone density change was weakly inversely correlated with change in the concentrations of BTMs. BTMs may prove useful in the monitoring of the response to lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.

BackgroundCurrently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown.MethodsPostmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided.ResultsBreast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04).ConclusionA 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

BackgroundCurrently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown.MethodsPostmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided.ResultsBreast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04).ConclusionA 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

BackgroundIn the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk.Methods and resultsIn this study, 8556 women 59 to 80 years of age with osteoporosis received lasofoxifene 0.25 mg/d, lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance (P=0.06 for both comparisons). Although both hazard ratios were

BackgroundIn the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk.Methods and resultsIn this study, 8556 women 59 to 80 years of age with osteoporosis received lasofoxifene 0.25 mg/d, lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance (P=0.06 for both comparisons). Although both hazard ratios were

BackgroundThe effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.MethodsIn this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.ResultsLasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.ConclusionsIn postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

BackgroundThe effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.MethodsIn this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.ResultsLasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.ConclusionsIn postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

The following case describes a 26-year-old female who presented to the emergency department with a nontrauamtic retrobulbar hematoma associated with warfarin toxicity. The application and limitations of focused bedside ocular sonography for this condition are discussed. [West J Emerg Med 2010; 11(2):208-210.]

New reduced-risk fungicides are highly effective in managing both pre- and postharvest diseases of stone fruit crops in California, and they have replaced most previously registered materials. These fungicides have a low impact on the environment, high specificity to target organisms, and low potential for groundwater contamination and human health risks. In stone fruit, they can be successfully used to manage brown rot blossom blight in a new delayed-bloom fungicide application program for low-precipitation years. In our studies, we found that fungicide treatments applied 1 to 14 days before harvest were also effective against preharvest brown rot and protected fruit from fungal decays initiated during harvest. Practices such as mixtures and rotations can be implemented to prevent resistance from developing and to ensure the lasting efficacy of these reduced-risk fungicides.