Primary cosmic-ray elemental spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass (CREAM) experiment since 2004. The third CREAM payload (CREAM-III) flew for 29 days ...during the 2007-2008 Antarctic season. Energies of incident particles above 1 TeV are measured with a calorimeter. Individual elements are clearly separated with a charge resolution of ∼0.12 e (in charge units) and ∼0.14 e for protons and helium nuclei, respectively, using two layers of silicon charge detectors. The measured proton and helium energy spectra at the top of the atmosphere are harder than other existing measurements at a few tens of GeV. The relative abundance of protons to helium nuclei is 9.53 0.03 for the range of 1 TeV/n to 63 TeV/n. This ratio is considerably smaller than other measurements at a few tens of GeV/n. The spectra become softer above ∼20 TeV. However, our statistical uncertainties are large at these energies and more data are needed.
Objective: To quantify the risk of developing dementia in those with mild cognitive impairment (MCI).
Method: Meta‐analysis of inception cohort studies.
Results: Forty‐one robust cohort studies ...were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to Alzheimer’s disease (AD) and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia, AD and VaD was 9.6%, 8.1% and 1.9%, respectively in specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non‐Mayo defined MCI and clinical trials are also reported.
Conclusion: The ACR is approximately 5–10% and most people with MCI will not progress to dementia even after 10 years of follow‐up.
The MAVEN spacecraft launched in November 2013, arrived at Mars in September 2014, and completed commissioning and began its one-Earth-year primary science mission in November 2014. The orbiter’s ...science objectives are to explore the interactions of the Sun and the solar wind with the Mars magnetosphere and upper atmosphere, to determine the structure of the upper atmosphere and ionosphere and the processes controlling it, to determine the escape rates from the upper atmosphere to space at the present epoch, and to measure properties that allow us to extrapolate these escape rates into the past to determine the total loss of atmospheric gas to space through time. These results will allow us to determine the importance of loss to space in changing the Mars climate and atmosphere through time, thereby providing important boundary conditions on the history of the habitability of Mars. The MAVEN spacecraft contains eight science instruments (with nine sensors) that measure the energy and particle input from the Sun into the Mars upper atmosphere, the response of the upper atmosphere to that input, and the resulting escape of gas to space. In addition, it contains an Electra relay that will allow it to relay commands and data between spacecraft on the surface and Earth.
Objective
To investigate whether people with subjective memory complaints (SMC) but no objective deficits are at increased risk of developing mild cognitive impairment (MCI) and dementia.
Method
...Major electronic databases were searched till 03/2014, and a meta‐analysis was conducted using inception cohort studies.
Results
Across 28 studies, there were 29 723 unique individuals (14 714 with SMC and 15 009 without SMC) (mean 71.6 years) followed on average for 4.8 years through to dementia. The annual conversion rate (ACR) of SMC to dementia was 2.33% (95% CI = 1.93%–2.78%) a relative risk (RR) of 2.07 (95% CI = 1.76–2.44) compared with those without SMC (n = 15 009). From 11 studies the ACR of developing MCI was 6.67% (95% CI = 4.70–8.95%). In long‐term studies over 4 years, 14.1% (9.67–19.1%) of people with SMC developed dementia and 26.6% (95% CI = 5.3–39.7) went on to develop MCI. The ACR from SMC to dementia and MCI were comparable in community and non‐community settings.
Conclusion
Older people with SMC but no objective complaints are twice as likely to develop dementia as individuals without SMC. Approximately 2.3% and 6.6% of older people with SMC will progress to dementia and MCI per year.
This narrative review considers the key challenges facing healthcare professionals and policymakers responsible for providing care to populations in relation to bone health. These challenges broadly ...fall into four distinct themes: (1) case finding and management of individuals at high risk of fracture, (2) public awareness of osteoporosis and fragility fractures, (3) reimbursement and health system policy and (4) epidemiology of fracture in the developing world. Findings from cohort studies, randomised controlled trials, systematic reviews and meta-analyses, in addition to current clinical guidelines, position papers and national and international audits, are summarised, with the intention of providing a prioritised approach to delivery of optimal bone health for all. Systematic approaches to case-finding individuals who are at high risk of sustaining fragility fractures are described. These include strategies and models of care intended to improve case finding for individuals who have sustained fragility fractures, those undergoing treatment with medicines which have an adverse effect on bone health and people who have diseases, whereby bone loss and, consequently, fragility fractures are a common comorbidity. Approaches to deliver primary fracture prevention in a clinically effective and cost-effective manner are also explored. Public awareness of osteoporosis is low worldwide. If older people are to be more pro-active in the management of their bone health, that needs to change. Effective disease awareness campaigns have been implemented in some countries but need to be undertaken in many more. A major need exists to improve awareness of the risk that osteoporosis poses to individuals who have initiated treatment, with the intention of improving adherence in the long term. A multisector effort is also required to support patients and their clinicians to have meaningful discussions concerning the risk-benefit ratio of osteoporosis treatment. With regard to prioritisation of fragility fracture prevention in national policy, there is much to be done. In the developing world, robust epidemiological estimates of fracture incidence are required to inform policy development. As the aging of the baby boomer generation is upon us, this review provides a comprehensive analysis of how bone health can be improved worldwide for all.
Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data ...connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.
The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines.
Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy–treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated.
Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
The Ras-Erk (extracellular signal-regulated kinase) pathway encodes information in its dynamics; the duration and frequency of Erk activity can specify distinct cell fates. To enable dynamic ...encoding, temporal information must be accurately transmitted from the plasma membrane to the nucleus. We used optogenetic profiling to show that both oncogenic B-Raf mutations and B-Raf inhibitors can cause corruption of this transmission, so that short pulses of input Ras activity are distorted into abnormally long Erk outputs. These changes can reshape downstream transcription and cell fates, resulting in improper decisions to proliferate. These findings illustrate how altered dynamic signal transmission properties, and not just constitutively increased signaling, can contribute to cell proliferation and perhaps cancer, and how optogenetic profiling can dissect mechanisms of signaling dysfunction in disease.
ABSTRACT
Near IR spectroscopic reverberation of Active Galactic Nuclei (AGN) potentially allows the infrared (IR) broad line region (BLR) to be reverberated alongside the disc and dust continua, ...while the spectra can also reveal details of dust astro-chemistry. Here, we describe results of a short pilot study (17 near-IR spectra over a 183 d period) for Mrk 509. The spectra give a luminosity-weighted dust radius of 〈Rd,lum〉 = 186 ± 4 light-days for blackbody (large grain dust), consistent with previous (photometric) reverberation campaigns, whereas carbon and silicate dust give much larger radii. We develop a method of calibrating spectral data in objects where the narrow lines are extended beyond the slit width. We demonstrate this by showing our resultant photometric band light curves are consistent with previous results, with a hot dust lag at >40 d in the K band, clearly different from the accretion disc response at <20 d in the z band. We place this limit of 40 d by demonstrating clearly that the modest variability that we do detect in the H and K band does not reverberate on time-scales of less than 40 d. We also extract the Pa β line light curve, and find a lag which is consistent with the optical BLR H β line of ∼70–90 d. This is important as direct imaging of the near-IR BLR is now possible in a few objects, so we need to understand its relation to the better studied optical BLR.
A process‐based treatment of ice supersaturation and ice nucleation is implemented in the National Center for Atmospheric Research Community Atmosphere Model (CAM). The new scheme is designed to ...allow (1) supersaturation with respect to ice, (2) ice nucleation by aerosol particles, and (3) ice cloud cover consistent with ice microphysics. The scheme is implemented with a two‐moment microphysics code and is used to evaluate ice cloud nucleation mechanisms and supersaturation in CAM. The new model is able to reproduce field observations of ice mass and mixed phase cloud occurrence better than previous versions. The model is able to reproduce observed patterns and frequency of ice supersaturation. Simulations indicate homogeneous freezing of sulfate and heterogeneous freezing on dust are both important ice nucleation mechanisms, in different regions. Simulated cloud forcing and climate is sensitive to different formulations of the ice microphysics. Arctic surface radiative fluxes are sensitive to the parameterization of ice clouds. These results indicate that ice clouds are potentially an important part of understanding cloud forcing and potential cloud feedbacks, particularly in the Arctic.
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