Electron acceleration inside the Earth's magnetosphere is required to explain increases in the ∼MeV radiation belt electron flux during magnetically disturbed periods. Recent studies show that ...electron acceleration by whistler mode chorus waves becomes most efficient just outside the plasmapause, near L = 4.5, where peaks in the electron phase space density are observed. We present CRRES data on the spatial distribution of chorus emissions during active conditions. The wave data are used to calculate the pitch angle and energy diffusion rates in three magnetic local time (MLT) sectors and to obtain a timescale for acceleration. We show that chorus emissions in the prenoon sector accelerate electrons most efficiently at latitudes above 15° for equatorial pitch angles between 20° and 60°. As electrons drift around the Earth, they are scattered to large pitch angles and further accelerated by chorus on the nightside in the equatorial region. The timescale to accelerate electrons by whistler mode chorus and increase the flux at 1 MeV by an order of magnitude is approximately 1 day, in agreement with satellite observations during the recovery phase of storms. During wave acceleration the electrons undergo many drift orbits and the resulting pitch angle distributions are energy‐dependent. Chorus scattering should produce pitch angle distributions that are either flat‐topped or butterfly‐shaped. The results provide strong support for the wave acceleration theory.
•Recorded locus coeruleus (LC) neurons in a rat model of Alzheimer's disease (AD).•TgF344-AD rats develop early endogenous LC tau pathology akin to human AD.•Six and 15 month TgF344-AD rats had ...reduced tonic LC firing.•LC neurons from 6-month TgF344-AD rats were hyperactive in response to footshock.•LC neuron dysfunction may contribute to AD symptoms.
Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-β (Aβ) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.
Following enhanced magnetic activity the fluxes of energetic electrons in the Earth's outer radiation belt gradually decay to quiet‐time levels. We use CRRES observations to estimate the energetic ...electron loss timescales and to identify the principal loss mechanisms. Gradual loss of energetic electrons in the region 3.0 ≤ L ≤ 5.0 occurs during quiet periods (Kp < 3−) following enhanced magnetic activity on timescales ranging from 1.5 to 3.5 days for 214 keV electrons to 5.5 to 6.5 days for 1.09 MeV electrons. The intervals of decay are associated with large average values of the ratio fpe/fce (>7), indicating that the decay takes place in the plasmasphere. We compute loss timescales for pitch‐angle scattering by plasmaspheric hiss using the PADIE code with wave properties based on CRRES observations. The resulting timescales suggest that pitch angle scattering by plasmaspheric hiss propagating at small or intermediate wave normal angles is responsible for electron loss over a wide range of energies and L shells. The region where hiss dominates loss is energy‐dependent, ranging from 3.5 ≤ L ≤ 5.0 at 214 keV to 3.0 ≤ L ≤ 4.0 at 1.09 MeV. Plasmaspheric hiss at large wave normal angles does not contribute significantly to the loss rates. At E = 1.09 MeV the loss timescales are overestimated by a factor of ∼5 for 4.5 ≤ L ≤ 5.0. We suggest that resonant wave‐particle interactions with EMIC waves, which become important at MeV energies for larger L (L > ∼4.5), may play a significant role in this region.
Aims
Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac ...myosin activator that enhances cardiomyocyte contraction.
Methods and results
We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.
Conclusions
Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.
Lipid injectable emulsions (ILEs) are complex pharmaceutical formulations intended as a source of energy and fatty acids for parenteral nutrition (PN) therapy. Part 1 of this series addressed issues ...associated with and safety recommendations pertaining to adult ILE use. Part 2 addresses ILE safety in neonatal and pediatric patients. Considerations for ILE use in the neonatal and pediatric populations differ from those of adults. For example, these patients often require higher doses compared with adult counterparts to support growth, development, and daily metabolic needs. ILE is also frequently administered as a separate infusion as opposed to in a total nutrient admixture owing to compatibility and stability issues and limitations to intravenous access in the neonatal and pediatric populations. ILE is the most frequent PN ingredient associated with PN errors occurring in the administration, prescribing, and transcribing processes. Concerns exist with use of in‐line filters and repackaging of commercial products for infusion. ILE use in neonatal and pediatric patients has been associated with both minor and major adverse effects, which most often occur with doses exceeding manufacturer recommendations. Gaps in ILE best practices for neonatal and pediatric patients predispose to errors in the PN use system. This paper describes safe‐use considerations for ILE products available in the United States in neonatal and pediatric patients, including indications, prescribing, order review, preparation, administration, and monitoring. This paper has been approved by the American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors.
Lychee pepper spot, a field disease affecting lychee fruit skin, pedicels and petioles, is caused by Colletotrichum siamense, a fungal pathogen within the gloeosporioides species complex. Members of ...Colletotrichum from the gloeosporioides species complex and occasionally those from the acutatum species complex also cause postharvest anthracnose of lychee. Pepper spot was first described in Australia many years after anthracnose on lychee was first described, giving rise to the hypothesis that a novel species or strain within the gloeosporioides species complex causes pepper spot. In the present study, 19 isolates of Colletotrichum spp., collected from pepper spot and anthracnose symptoms on lychee fruit, representing 13 different genotypes across five species, were inoculated onto lychee fruit in the field or on detached fruit in the laboratory, to understand more about their pathogenic diversity. We found that symptoms were specific to genotype of the pathogen, as three genetically similar isolates of C. siamense consistently caused pepper spot and anthracnose, whilst other isolates caused anthracnose only. Cross‐inoculation studies on detached fruit of lychee, banana, avocado and mango also provided some evidence of host specialization in isolates of C. siamense infecting lychee in Australia. Our experiments provided further evidence that detached fruit assays cannot be used as a reliable proxy for field inoculation studies. This research confirms that C. siamense is a causal agent of both lychee pepper spot and lychee anthracnose in Australia, and Colletotrichum alienum and Colletotrichum queenslandicum are reported as causal agents of anthracnose of lychee for the first time.
Pathogenicity on lychee and population genomics show that taxa in the gloeosporioides species complex are predominantly clonal, and symptoms and host range are linked to genotype.
Lipid injectable emulsions (ILEs) are complex pharmaceutical formulations used as a source of energy and essential fatty acids in parenteral nutrition. Issues associated with ILE use are distinctly ...different from oral fat and arise from emulsion stability, dose, and infusion tolerance. Since 1975, soybean oil has been the consistent source oil used in ILE formulations in the US. Partly because of safety concerns with the soybean‐based ILE and frequent and long‐standing problems with product inventory shortages, new ILE products have become available. Gaps in ILE best practices create a risk for ILE safety errors in prescribing, compounding, and administration of these products. This paper provides information on appropriate indications, dosing, and methods to avoid potential errors with ILE products in the US. This paper (Part 1) will focus on ILE background, information, and recommendations for adult patients, whereas Part 2 of this series will focus on neonatal and pediatric patient–specific information.
Compared with the general population, carriers of germline mutations in RB1 who survive retinoblastoma (i.e., hereditary retinoblastoma survivors) are at increased risk of early-onset second cancers, ...particularly sarcomas, brain tumors, and melanoma. However, their risks for the epithelial cancers that commonly occur after age 50 years are not known.
We used hospital records to identify British retinoblastoma survivors born between 1873 and 1950, a period when few British retinoblastoma patients received high-dose radiotherapy. Cancers and deaths were identified by linkage with national registration records. All statistical tests were two-sided.
We could trace the cancer histories of 144 survivors of hereditary retinoblastoma. From age 25 to age 84, there were 58 subsequent cancers, for a cumulative cancer incidence of 68.8% (95% confidence interval CI = 48.0% to 87.4%) and a cumulative cancer mortality of 56.3% (95% CI = 40.5% to 73.3%). Only eight of the 58 cancers were of bone or soft tissue, in marked contrast to findings from contemporary studies of American patients treated with external beam radiotherapy, among whom most second tumors are sarcomas. Compared with the general population, hereditary retinoblastoma survivors had higher mortality from lung cancer (standardized mortality ratio SMR = 7.01, 95% CI = 3.83 to 11.76), bladder cancer (SMR = 26.31, 95% CI = 8.54 to 61.41), and all other epithelial cancers combined (SMR = 3.29, 95% CI = 1.64 to 5.89). The overall standardized mortality ratio for epithelial cancer was inversely proportional to the approximate square of age (exponent of age = -2.1, 95% CI = -3.6 to -0.7), declining from 11.32 (95% CI = 4.15 to 24.64) at age 25-44 to 2.83 (95% CI = 1.04 to 6.16) at age 65-84.
Survivors of hereditary retinoblastoma who are not exposed to high-dose radiotherapy have a high lifetime risk of developing a late-onset epithelial cancer. Most of the excess cancer risks in hereditary retinoblastoma survivors might be preventable by limiting exposures to DNA damaging agents (radiotherapy, tobacco, and UV light).
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