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The problem on constructing new time-effective characteristics of a linear viscoelastic body is considered. The initial medium is modeled as a viscoelastic composite. One its part has properties determined by time-effective moduli of the Lagrangian type, but the other part has properties determined by moduli of the Castigliano type. This model makes it possible to employ the methods of mechanics of composite materials, for example, to formulate the effective Voigt and Reuss moduli and to construct iterative transformations narrowing the Voigt and Reuss fork. These transformations are constructed in such a way that, at each iteration, the inequalities following from the minimum total potential energy principle and the theorem of complementary work are satisfied for the effective moduli. It is shown that, at each moment of time t, the sequences of iteratively transformed Voigt and Reuss moduli converge to the same limit, equal to the geometric mean of their initial values. By the example of the problem on bending of a viscoelastic plate, the approximate solutions obtained on the basis of the new time-effective characteristics found, are compared with an analytical solution. Their good agreement points to a high accuracy of the approximate solutions.

Energy coupling between the solar wind and the Earth's magnetosphere can affect the electron population in the outer radiation belt. However, the precise role of different internal and external mechanisms that leads to changes of the relativistic electron population is not entirely known. This paper describes how ultralow frequency (ULF) wave activity during the passage of Alfvenic solar wind streams contributes to the global recovery of the relativistic electron population in the outer radiation belt. To investigate the contribution of the ULF waves, we searched the Van Allen Probes data for a period in which we can clearly distinguish the enhancement of electron fluxes from the background. We found that the global recovery that started on 22 September 2014, which coincides with the corotating interaction region preceding a high‐speed stream and the occurrence of persistent substorm activity, provides an excellent scenario to explore the contribution of ULF waves. To support our analyses, we employed ground‐ and space‐based observational data and global magnetohydrodynamic simulations and calculated the ULF wave radial diffusion coefficients employing an empirical model. Observations show a gradual increase of electron fluxes in the outer radiation belt and a concomitant enhancement of ULF activity that spreads from higher to lower L‐shells. Magnetohydrodynamic simulation results agree with observed ULF wave activity in the magnetotail, which leads to both fast and Alfven modes in the magnetospheric nightside sector. The observations agree with the empirical model and are confirmed by phase space density calculations for this global recovery period.

A moderate geomagnetic storm (Sym/H similar to-100 nT) during June 28 and 29, 2013 was studied using Comprehensive Inner Magnetosphere-Ionosphere (CIMI) simulations and results were compared with Two wide-angle Imaging Neutral-atom Spectrometers (TWINS) observations of the spatial and temporal evolution of ring current (RC) ions including ion pressure, anisotropy, intensity, and median energy. At the onset of the storm (11:00 UT on June 28), TWINS ion pressure peaks were located radially outward and dusk ward compared to CIMI. During the main phase and the recovery phase (06:00 UT on June 28 to 16:00 UT on June 29), southward IMF Bz and rapid AE index fluctuations were observed indicating substorm ion injections and TWINS observed multiple ion pressure peaks at least one of which were found to be close to the locations of CIMI ion pressure peaks. TWINS also observed regions of parallel pressure anisotropy near pre-midnight sectors. The RC ion energies in TWINS were found to be very low (

We present a new expansion of the Polar Wind Outflow Model (PWOM) to include kinetic ions using the Particle-in-Cell (PIC) approach with Monte Carlo collisions. This implementation uses the original hydrodynamic solution at low altitudes for efficiency, and couples to the kinetic solution at higher altitudes to account for kinetic effects important for ionospheric outflow. The modeling approach also includes wave-particle interactions, suprathermal electrons, and an hybrid parallel computing approach combining shared and distributed memory paralellization. The resulting model is thus a comprehensive, global, model of ionospheric outflow that can be run efficiently on large supercomputing clusters. We demonstrate the model’s capability to study a range of problems starting with the comparison of kinetic and hydrodynamic solutions along a single field line in the sunlit polar cap, and progressing to the altitude evolution of the ion conic distribution in the cusp region. The interplay between convection and the cusp on the global outflow solution is also examined. Finally, we demonstrate the impact of these new model features on the magnetosphere by presenting the first 2-way coupled ionospheric outflow-magnetosphere calculation including kinetic ion effects.

Introduction Neuropsychiatric symptoms (NPS) are common at all stages of Alzheimer disease (AD). Delusions in AD are associated with negative clinical consequences and may signal rapid disease progression. Hence, we sought to determine the prevalence of delusions in drug-naive (no cholinesterase inhibitor or neuroleptic medications) AD patients. Methods In this meta-analysis, a search of the EMBASE, MEDLINE, and PsycINFO databases was performed. We selected studies reporting delusion prevalence measured by the Neuropsychiatric Inventory (NPI) in drug-naive AD patients. An aggregate delusion event rate with 95% confidence interval (CI) was calculated. The I2 statistic was used to assess the magnitude of between-study heterogeneity. Single variable meta-regressions allowed examination of the effect of moderating factors and heterogeneity. Quantitative measures were used to appraise for publication bias. Results We identified 6 studies with 591 participants allowing calculation of the aggregate delusional prevalence rate. Irrespective of dementia severity, the aggregate event rate for delusions was 29.1% (95% CI: 20–41%; I2 = 84.59). No publication bias was observed. Conclusion This meta-analysis calculates a 29.1% prevalence rate of delusions in AD patients. There is a trend towards increasing delusion prevalence in concordance with increasing severity of dementia. Given delusions are associated with poorer outcomes, the obtained prevalence should motivate clinicians to screen carefully for delusions. Current literature limitations warrant future studies, with sub-analyses on dementia severity, and other neurobiological factors known to influence the presence of delusions.

Energetic O+ ions (tens of keV) rapidly increase in the inner magnetosphere and contribute significantly to the ring current during substorms. Previously, two source regions of the energetic O+ ions have been proposed. The first one is the dayside polar region. Ions from the dayside polar region are transported to the lobe; then they are injected to the nightside plasma sheet during substorm expansion phase. The second one is the nightside aurora region. After the substorm onset, energetic O+ ions are extracted from the ionosphere with the auroral acceleration processes, and the O+ ions are directly supplied to the nightside plasma sheet. We investigated the relative importance of these two regions on supplying the energetic O+ ions in the inner magnetosphere. We performed a test particle simulation in global MHD electromagnetic fields. We obtained the following results. (1) During the substorm growth phase, O+ ions at tens of eV are extracted from the dayside polar region, resulting in the enhancement of the warm O+ ions (hundreds of eV) in the lobe. After the substorm onset, the warm O+ ions are nonadiabatically accelerated to tens of keV and injected to the inner magnetosphere. These O+ ions contribute to most of the O+ ring current. (2) O+ ions at less than a few keVs are supplied from the nightside aurora region to the plasma sheet. However, their contribution to the O+ ring current remains small. From the results, we concluded that the main source of the energetic O+ ions is the dayside polar region.

A scheme is suggested and tested for forecasting severe space weather (SvSW) using solar wind velocity (V) and the north-south component (Bz) of the interplanetary magnetic field (IMF) measured using the ACE (Advanced Composition Explorer) satellite from 1998 to 2016. SvSW has caused all known electric power outages and telegraph system failures. Earlier SvSW events such as the Carrington event of 1859, Quebec event of 1989 and an event in 1958 are included with information from the literature. Dst storms are used as references to identify 89 major space weather events (DstMin ≤ -100 nT) in 1998-2016. The coincidence of high CME front (or CME shock) velocity ΔV (sudden increase in V over the background by over 275 km/s) and sufficiently large Bz southward at the time of the ΔV increase is associated with SvSW; and their product (ΔV x Bz) is found to exhibit a large negative spike at the speed increase. Such a product (ΔV x Bz) exceeding a threshold seems suitable for forecasting SvSW. However, the coincidence of high V (not containing ΔV) and large Bz southward does not correspond to SvSW, indicating the importance of the impulsive action of large Bz southward and high ΔV coming through when they coincide. The need for the coincidence is verified using the CRCM (Comprehensive Ring Current Model) model, that produces extreme Dst storms (

Background and aims Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo. Approach and results Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4α) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS. Conclusions Our data show that telomere dysfunction acts as a major regulator of HNF4α during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.

Telomere attrition is a risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cell lines (hESCs) harboring a clinically relevant mutation in telomerase (DKC1_A353V) and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol, that resembles hepatocyte development in vivo. Our results show that while telomerase is highly expressed in hESCs, it is quickly silenced, due to TERT down-regulation, after endoderm differentiation, and completely absent in in vitro derived hepatocytes, similarly to what is observed in primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte-derivation, as measured by expression of specific markers, as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening induces down regulation of the human hepatocyte nuclear factor 4α (HNF4α), in a p53 dependent manner. Telomerase reactivation, as well as p53 silencing, rescued hepatocyte formation in telomerase mutants. Likewise, conditional expression of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and p53 stabilization, successfully restored hepatocyte formation from hESCS.ConclusionsCombined, our data shows that telomere dysfunction acts a major regulator of HNF4α during hepatocyte development and function, pointing to a potential novel target for the clinical management of liver disease in telomere-syndrome patients.

Reduced levels of TERC, the telomerase RNA component, cause dyskeratosis congenita (DC) in patients harboring mutations in TERC, PARN, NOP10, NHP2, NAF1, or DKC1. Inhibition of the noncanonical poly(A) polymerase PAPD5, or the exosome RNA degradation complex, partially restores TERC levels in immortalized DKC1 mutant cells, but it remains unknown if modulation of posttranscriptional processing of TERC could improve hematopoietic output in DC. We used human embryonic stem cells (hESCs) with a common dyskerin mutation (DKC1_A353V), which have defective telomere maintenance and reduced definitive hematopoietic potential, to understand the effects of reducing EXOSC3 activity, or silencing PAPD5-mediated oligoadenylation, on hematopoietic progenitor specification and function in DC. Reduction of EXOSC3 or PAPD5 levels in DKC1 mutant hESCs led to functional improvements in TERC levels and telomerase activity, with concomitant telomere elongation and reduced levels of DNA damage signaling. Interestingly, the silencing of PAPD5, but not EXOSC3, significantly restored definitive hematopoietic potential in DKC1 mutant cells. Mechanistically, we show that PAPD5 inhibition is sustained in differentiated CD34+ cells, with a concomitant increase in mature, functional, forms of TERC, indicating that regulation of PAPD5 is a potential strategy to reverse hematologic dysfunction in DC patients.

A flux dropout is a sudden and sizable decrease in the energetic electron population of the outer radiation belt on the time scale of a few hours. We simulated a flux dropout of highly relativistic 2.5 MeV electrons using the Radiation Belt Environment model, incorporating the pitch angle diffusion coefficients caused by electromagnetic ion cyclotron (EMIC) waves for the geomagnetic storm events of 23-26 October 2002. This simulation showed a remarkable decrease in the 2.5 MeV electron flux during main phase of the storm, compared to those without EMIC waves. This decrease was independent of magnetopause shadowing or drift loss to the magnetopause. We suggest that the flux decrease was likely to be primarily due to pitch angle scattering to the loss cone by EMIC waves. Furthermore, the 2.5 MeV electron flux calculated with EMIC waves correspond very well with that observed from Solar Anomalous and Magnetospheric Particle EXplorer spacecraft. EMIC wave scattering is therefore likely one of the key mechanisms to understand flux dropouts. We modeled EMIC wave intensities by the Kp index. However, the calculated dropout is a several hours earlier than the observed one. We propose that Kp is not the best parameter to predict EMIC waves.

Aims This study aimed to evaluate the associations between types of night shift work and different indices of obesity using the baseline information from a prospective cohort study of night shift workers in China. Methods A total of 3,871 workers from five companies were recruited from the baseline survey. A structured self-administered questionnaire was employed to collect the participants' demographic information, lifetime working history, and lifestyle habits. Participants were grouped into rotating, permanent and irregular night shift work groups. Anthropometric parameters were assessed by healthcare professionals. Multiple logistic regression models were used to evaluate the associations between night shift work and different indices of obesity. Results Night shift workers had increased risk of overweight and obesity, and odds ratios (ORs) were 1.17 (95% CI, 0.97-1.41) and 1.27 (95% CI, 0.74-2.18), respectively. Abdominal obesity had a significant but marginal association with night shift work (OR = 1.20, 95% CI, 1.01-1.43). A positive gradient between the number of years of night shift work and overweight or abdominal obesity was observed. Permanent night shift work showed the highest odds of being overweight (OR = 3.94, 95% CI, 1.40-11.03) and having increased abdominal obesity (OR = 3.34, 95% CI, 1.19-9.37). Irregular night shift work was also significantly associated with overweight (OR = 1.56, 95% CI, 1.13-2.14), but its association with abdominal obesity was borderline (OR = 1.26, 95% CI, 0.94-1.69). By contrast, the association between rotating night shift work and these parameters was not significant. Conclusion Permanent and irregular night shift work were more likely to be associated with overweight or abdominal obesity than rotating night shift work. These associations need to be verified in prospective cohort studies.

The caseinolytic peptidase P (ClpP) is the endopeptidase component of the mitochondrial matrix ATP-dependent ClpXP protease. ClpP degrades unfolded proteins to maintain mitochondrial protein homeostasis and is involved in the initiation of the mitochondrial unfolded protein response (UPR(mt)). Outside of an integral role in the UPR(mt), the cellular function of ClpP is not well characterized in mammalian cells. To investigate the role of ClpP in mitochondrial function, we generated C2C12 muscle cells that are deficient in ClpP using siRNA or stable knockdown using lentiviral transduction. Reduction of ClpP levels by ~70% in C2C12 muscle cells resulted in a number of mitochondrial alterations including reduced mitochondrial respiration and reduced oxygen consumption rate in response to electron transport chain (ETC) complex I and II substrates. The reduction in ClpP altered mitochondrial morphology, changed the expression level of mitochondrial fission protein Drp1 and blunted UPR(mt) induction. In addition, ClpP deficient cells showed increased generation of reactive oxygen species (ROS) and decreased membrane potential. At the cellular level, reduction of ClpP impaired myoblast differentiation, cell proliferation and elevated phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) suggesting an inhibition of translation. Our study is the first to define the effects of ClpP deficiency on mitochondrial function in muscle cells in vitro. In addition, we have uncovered novel effects of ClpP on mitochondrial morphology, cell proliferation and protein translation pathways in muscle cells.

From 2 to 5 UT on 14 November 2012, the Van Allen Probes observed repeated particle flux dropouts during the main phase of a geomagnetic storm as the satellites traversed the post-midnight to dawnside inner magnetosphere. Each flux dropout corresponded to an abrupt change in the magnetic topology, i.e., from a more dipolar configuration to a configuration with magnetic field lines stretched in the dawn-dusk direction. Geosynchronous GOES spacecraft located in the dusk and near-midnight sectors and the LANL constellation with wide local time coverage also observed repeated flux dropouts and stretched field lines with similar occurrence patterns to those of the Van Allen Probe events. THEMIS recorded multiple transient abrupt expansions of the evening-side magnetopause ∼20–30 min prior to the sequential Van Allen Probes observations. Ground-based magnetograms and all sky images demonstrate repeatable features in conjunction with the dropouts. We combine the various in situ and ground-based measurements to define and understand the global spatiotemporal features associated with the dropouts observed by the Van Allen Probes. We discuss various proposed hypotheses for the mechanism that plausibly caused this storm-time dropout event as well as formulate a new hypothesis that explains the combined in situ and ground-based observations: the earthward motion of magnetic flux ropes containing lobe plasmas that form along an extended magnetotail reconnection line in the near-Earth plasma sheet.

Summary Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.

Objective To summarize the effect of antipsychotics for preventing postoperative delirium. Design We conducted a literature search using Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and clinicaltrials.gov. We included randomized controlled trials of adults undergoing surgery who were given antipsychotics to prevent postoperative delirium. Quality was assessed via the Cochrane risk of bias tool. Random-effects meta-analysis and meta-regression were conducted. Q-statistics and I2 were used for assessment of heterogeneity. The main outcome was delirium incidence using validated definitions. Results A total of 1710 subjects were included, with a mean age ranging from 60.7 to 86.4 years. Antipsychotics reduced the incidence of postoperative delirium with the global effect-size estimate (weighted odds ratio) using the random effects model of 0.44 (95% confidence interval: 0.28–0.70; N = 6; Q-value: 16, p-value 0.0005; I2 = 69%). Significant heterogeneity existed with the pooled global effect of delirium incidence; however, meta-regression allowed us to test both treatment-level and patient-level explanations for significant between-study variance. Baseline risk for delirium was found to be a significant contributor to study heterogeneity, and meta-regression suggested that antipsychotic type and dosage were two of the several treatment-level factors that also may have led to heterogeneity. Our analysis implied the presence of a breakeven baseline level of delirium risk below which preventive treatment with antipsychotics might prove ineffective. Conclusions Within the limits of few randomized controlled trials, antipsychotics appeared to reduce the incidence of postoperative delirium in several surgical settings, predominantly orthopedic and for those at higher risk for delirium. Copyright © 2015 John Wiley & Sons, Ltd.

To study the magnetopause on both MHD and kinetic scales, we have analyzed two Time History of Events and Macroscale Interactions during Substorms/Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun magnetopause crossings under steady slow-solar wind and minimum magnetic shear conditions. These events approximate a ground state of the magnetospheric boundary with minimum influences from large-solar wind disturbances and magnetic reconnection. Our observations reveal evidence for the Kelvin-Helmholtz instability, the quasi-periodicity of magnetopause surface waves accompanied by highly asymmetrical plasma signatures between the inbound (from magnetosheath to low-latitude boundary layer (LLBL)) and the outbound (from LLBL to magnetosheath) magnetopause crossings. Stronger plasma and magnetic gradients were observed during the outbound crossings but more gradual and volatile variations at higher frequencies during the inbounds. The scale lengths of the magnetic and plasma gradients were comparable or less than the proton gyroradius. Enhancements of lower hybrid waves occurred at the locations of strong gradients or variations. We interpreted the collocations of the lower hybrid waves and plasma gradients and their variations in terms of (1) lower hybrid instabilities that directly convert solar wind flow energy into lower hybrid waves and other wave modes in the LLBL, or (2) Kelvin-Helmholtz instability and magnetic reconnection which produce the conditions for the lower hybrid instabilities to grow. The rate of ion diffusion across the magnetopause caused by the lower hybrid instability is marginally sufficient to populate the LLBL. The diffusion coefficient of O+ is ~30 times larger than that of H+. The lower hybrid waves could contribute to the energy dissipation at plasma gradients in magnetopause surface wave structures and limit Kelvin-Helmholtz instability growth further downstream.

Global, ion equatorial flux distributions and energy spectra are presented from stereoscopic Two Wide-Angle Imaging Neutral-Atom Spectrometers (TWINS) 1 and TWINS 2 energetic neutral atom (ENA) images for two time periods, 29 May 2010, 1330–1430 UT and 26 May 2011, 1645–1715 UT. The first is just after the main phase of a weak (minimum SYM/H ≈ −70 to −80 nT) corotating interaction region-driven geomagnetic storm. The second is during a relatively quiet period. The global ion distributions show multiple spatial peaks that are coincident with peaks in the AE index. The energy spectra have a primary maximum in the 15–20 keV range. Below the energy maximum, the flux is Maxwellian. Above the main maximum, the flux is either significantly below that of a Maxwellian or has a second component with a maximum in the 40–50 keV range. For the 29 May 2010, 1330–1430 UT time period, the flux from the TWINS stereoscopic images is compared to the results from TWINS 1 and TWINS 2 alone illustrating the advantage of stereoscopic viewing. The flux deconvolved from the TWINS images also shows spatial and temporal correlations with Time History of Events and Macroscale Interactions during Substorms (THEMIS) in situ measurements. Magnetic field dipolarizations observed by GOES support the existence of a peak in the ion flux in the midnight/dawn sector. In summary, increased spatial resolution from TWINS stereoscopic ENA images is demonstrated. Multiple peaks in the ion flux of trapped particles in the ring current are observed. THEMIS electrostatic analyzer in situ ion flux measurements and GOES geosynchronous magnetic field measurements are consistent with the spatial and temporal structure obtained.

Background The effect of a multi-faceted handoff strategy in a high volume internal medicine inpatient setting on process and patient outcomes has not been clearly established. We set out to determine if a multi-faceted handoff intervention consisting of education, standardized handoff procedures, including fixed time and location for face-to-face handoff would result in improved rates of handoff compared with usual practice. We also evaluated resident satisfaction, health resource utilization and clinical outcomes. Methods This was a cluster randomized controlled trial in a large academic tertiary care center with 18 inpatient internal medicine ward teams from January-April 2013. We randomized nine inpatient teams to an intervention where they received an education session standardizing who and how to handoff patients, with practice and feedback from facilitators. The control group of 9 teams continued usual non-standardized handoffs. The primary process outcome was the rate of patients handed over per 1000 patient nights. Other process outcomes included perceptions of inadequate handoff by overnight physicians, resource utilization overnight and hospital length of stay. Clinical outcomes included medical errors, frequency of patients requiring higher level of care overnight, and in-hospital mortality. Results The intervention group demonstrated a significant increase in the rate of patients handed over to the overnight physician (62.90/1000 person-nights vs. 46.86/1000 person-nights, p = 0.002). There was no significant difference in other process outcomes except resource utilization was increased in the intervention group (26.35/1000 person-days vs. 17.57/1000 person-days, p-value = 0.01). There was no significant difference between groups in medical errors (4.8% vs. 4.1%), need for higher level of care or in hospital mortality. Limitations include a dependence of accurate record keeping by the overnight physician, the possibility of cross-contamination in the handoff process, analysis at the cluster level and an overall low number of clinical events. Conclusions Implementation of a multi-faceted resident handoff intervention did not result in a significant improvement in patient safety although did improve number of patients handed off. Novel methods to improve handoff need to be explored. Trial registration Registered at ClinicalTrials.gov: NCT01796756.

Summary Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients., Graphical Abstract, Highlights • CRISPR/Cas9 was used to generate different DC-associated mutations in hESCs • Telomere shortening specifically impairs definitive hematopoietic specification • Genetic instability and p53 activation regulate hematopoietic specification in DC • In vitro hematopoietic failure resembles phenotypes of aplastic anemia in DC, By directly assessing primitive or definitive hematopoiesis derived from telomerase-mutant hESCs, Batista and colleagues show that telomere shortening specifically impairs definitive hematopoietic potential, while primitive hematopoiesis is instead enhanced. This system offers the unprecedented capability to study hematopoietic failure and suggests that bone marrow failure in DC patients is reversible.

Rapamycin, a drug that has been shown to increase lifespan in mice, inhibits the target of rapamycin (TOR) pathway, a major pathway that regulates cell growth and energy status. It has been hypothesized that rapamycin and dietary restriction (DR) extend lifespan through similar mechanisms/pathways. Using microarray analysis, we compared the transcriptome of white adipose tissue from mice fed rapamycin or DR-diet for six months. Multidimensional scaling and heatmap analyses showed that rapamycin had essentially no effect on the transcriptome as compared to DR. For example, only six transcripts were significantly altered by rapamycin while mice fed DR showed a significant change in over 1,000 transcripts. Using ingenuity pathway analysis, we found that stearate biosynthesis and circadian rhythm signaling were significantly changed by DR. Our findings showing that DR, but not rapamycin, have an effect on the transcriptome of the adipose tissue, suggesting that these two manipulations increase lifespan through different mechanisms/pathways.

Following a long period of observation and investigation beginning in the early 1970s, it has been firmly established that Earth׳s magnetosphere is defined as much by the geogenic plasma within it as by the geomagnetic field. This plasma is not confined to the ionosphere proper, defined as the region within a few density scale heights of the F-region plasma density peak. Rather, it fills the flux tubes on which it is created, and circulates throughout the magnetosphere in a pattern driven by solar wind plasma that becomes magnetically connected to the ionosphere by reconnection through the dayside magnetopause. Under certain solar wind conditions, plasma and field energy is stored in the magnetotail rather than being smoothly recirculated back to the dayside. Its release into the downstream solar wind is produced by magnetotail disconnection of stored plasma and fields both continuously and in the form of discrete plasmoids, with associated generation of energetic Earthward-moving bursty bulk flows and injection fronts. A new generation of global circulation models is showing us that outflowing ionospheric plasmas, especially O + , load the system in a different way than the resistive F-region load of currents dissipating energy in the plasma and atmospheric neutral gas. The extended ionospheric load is reactive to the primary dissipation, forming a time-delayed feedback loop within the system. That sets up or intensifies bursty transient behaviors that would be weaker or absent if the ionosphere did not “strike back” when stimulated. Understanding this response appears to be a necessary, if not sufficient, condition for us to gain accurate predictive capability for space weather. However, full predictive understanding of outflow and incorporation into global simulations requires a clear observational and theoretical identification of the causal mechanisms of the outflows. This remains elusive and requires a dedicated mission effort.

Coronal mass ejections (CMEs) and corotating interaction regions associated with high speed solar wind streams (CIR/HSSs) drive geomagnetic storms in the terrestrial magnetosphere. Each type of storm driver yields different dynamics of storm evolution. We present results from comparative superposed epoch analyses of global ion temperatures calculated from TWINS energetic neutral atom (ENA) data and simulations using the comprehensive ring current model (CRCM). During the June 2008–April 2012 timeframe, 48 geomagnetic storms (minimum Dst≤−40 nT) occurred. Of these, 21 storms were CME-driven and 15 were driven by CIR/HSSs. Superposed epoch analysis results demonstrate that ion temperatures increase during the recovery phase of CIR/HSS-driven storms, while ions are rapidly heated at the commencement of CME-driven storms then cool over the main phase, particularly for intense (minimum Dst≤−78 nT) CME-driven storms. Higher energy ions are convected to lower L-shells during CME-driven storms, while CIR/HSS-driven storms tend to have average ion temperatures that are higher on the dayside than nightside.

We have integrated dynamic, spatiotemporally resolved ion temperature boundary conditions into the Comprehensive Ring Current Model (CRCM), which are based on 2-D equatorial maps derived from the Two Wide-Angle Imaging Neutral-Atom Spectrometers (TWINS) energetic neutral atom (ENA) data. The high-speed stream-driven event on 22 July 2009 is simulated and compared against an identical simulation using a statistically derived boundary condition model. ENA-derived temperatures allow users to include event-specific observations associated with a dynamic plasma sheet. This method also provides temperatures in the important region between geosynchronous orbit and the plasma sheet, a region which existing empirical models exclude. We find that the spatial and energy distributions of ring current flux and pressure have sensitive dependence on boundary conditions during this event. The coupling of boundary conditions to the time history of the convection field strength also plays an important role by throttling the influence of the boundary plasma on the inner magnetosphere. Simulated moments and spectra from our simulations are compared with remotely imaged ion temperatures from TWINS and also in situ energy spectra and temperature moments from Time History of Events and Macroscale Interactions during Substorms-D. Storm time dusk-dawn asymmetries consistent with observational data, such as Zhang et al. (2006), are reproduced well when CRCM is provided with the event-specific boundary model. A hot localized structure observed by TWINS at geosynchronous midnight during a strong northward interplanetary magnetic field interval is also reproduced with this boundary model, whereas the empirical boundary model fails to yield this feature.

We have developed a technique for estimating the temporal evolution of the plasmaspheric helium ion density based on a sequence of extreme ultraviolet (EUV) data obtained from the IMAGE satellite. In the proposed technique, the estimation is obtained by incorporating EUV images from IMAGE into a two-dimensional fluid model of the plasmasphere using a data assimilation approach based on the ensemble transform Kalman filter. Since the motion and the spatial structure of the helium plasmasphere is strongly controlled by the electric field in the inner magnetosphere, the electric field around the plasmapause can also be estimated using the ensemble transform Kalman filter. We performed an experiment using synthetic images that were generated from the same numerical model under a certain condition. It was confirmed that the condition that generated the synthetic images was successfully reproduced. We also present some results obtained using real EUV imaging data. Finally, we discuss the possibility of estimating the density profile along a magnetic field line. Since each EUV image was taken from a different direction due to the motion of the IMAGE satellite, we could obtain the information on the density profile along a field line by combining multiple images.

Dietary restriction (DR) is the gold standard intervention used to delay aging, and much recent research has focused on the identification of possible DR mimetics. Energy sensing pathways, including insulin/IGF1 signaling, sirtuins, and mammalian Target of Rapamycin (mTOR), have been proposed as pathways involved in the antiaging actions of DR, and compounds that affect these pathways have been suggested to act as DR mimetics, including metformin (insulin/IGF1 signaling), resveratrol (sirtuins), and rapamycin (mTOR). Rapamycin is a promising DR mimetic because it significantly increases both health span and life span in mice. Unfortunately, rapamycin also leads to some negative effects, foremost among which is the induction of insulin resistance, potentially limiting its translation into humans. To begin clarifying the mechanism(s) involved in insulin resistance induced by rapamycin, we compared several aspects of liver metabolism in mice treated with DR or rapamycin for 6 months. Our data suggest that although both DR and rapamycin inhibit lipogenesis, activate lipolysis, and increased serum levels of nonesterified fatty acids, only DR further activates β-oxidation of the fatty acids leading to the production of ketone bodies.

During large geomagnetic storms (Dst ≤−100 nT), oxygen can become a significant component of the energetic particles of the inner magnetosphere. Until recently, there were no available global observations of the medium energy ( 52 keV) O ENAs.

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.

5-aminosalicylates (5-ASA) remain an important strategy in the induction and maintenance of remission of inflammatory bowel diseases especially in ulcerative colitis. The prototypical drug of this class, sulfasalazine is generally well tolerated with severe hypersensitivity reactions and hepatotoxicity also described within the literature. When approaching a patient with an adverse reaction to 5-ASA, it can be difficult to differentiate clinically between a sulfa allergy versus a 5-ASA allergy versus a malignancy. We report on a case with initial signs and symptoms suggestive of a sulfa/5-ASA allergy that was subsequently found to be malignant in nature.

[1] We have recently extended the global magnetohydrodynamic (MHD) model BATS-R-US to account for pressure anisotropy. Since the inner magnetosphere dynamics cannot be fully described even by anisotropic MHD, we coupled our anisotropic MHD model with two inner magnetospheric models: the Rice Convection Model (RCM) and the Comprehensive Ring Current Model (CRCM). The coupled models provide better representations of the near-Earth plasma, especially during geomagnetic storms. In this paper, we present the two-way coupling algorithms with both ring current models. The major difference between these two couplings is that the RCM assumes isotropic and constant pressures along closed field lines, while the CRCM resolves pitch angle anisotropy. For model validation, we report global magnetosphere simulations performed by the coupled models. The simulation results are compared to the results given by the coupled isotropic MHD and ring current models. We find that in the global MHD simulations coupled with ring current models, pressure anisotropy results in a thinner magnetosheath, a shorter tail, a much smaller Earthward plasma jet from the tail reconnection site, and is also important in controlling the magnetic field configuration. The comparisons with satellite data for the magnetospheric event simulations show improvements on reproducing the measured tail magnetic field and inner magnetospheric flow velocity when including pressure anisotropy in the ring current model coupled global MHD model.