Three decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, the US Food and Drug Administration acknowledge the syndrome as ...the leading cause of transfusion-related mortality. Understanding of the pathogenesis of TRALI has resulted in the design of preventive strategies from a blood-bank perspective. A major breakthrough in efforts to reduce the incidence of TRALI has been to exclude female donors of products with high plasma volume, resulting in a decrease of roughly two-thirds in incidence. However, this strategy has not completely eradicated the complication. In the past few years, research has identified patient-related risk factors for the onset of TRALI, which have empowered physicians to take an individualised approach to patients who need transfusion.
SUMMARY
Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been ...emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P ≤ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P ≤ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P ≤ 0.024 and DIS P ≤ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.
Evidence that extreme rainfall intensity is increasing at the global scale has strengthened considerably in recent years. Research now indicates that the greatest increases are likely to occur in ...short‐duration storms lasting less than a day, potentially leading to an increase in the magnitude and frequency of flash floods. This review examines the evidence for subdaily extreme rainfall intensification due to anthropogenic climate change and describes our current physical understanding of the association between subdaily extreme rainfall intensity and atmospheric temperature. We also examine the nature, quality, and quantity of information needed to allow society to adapt successfully to predicted future changes, and discuss the roles of observational and modeling studies in helping us to better understand the physical processes that can influence subdaily extreme rainfall characteristics. We conclude by describing the types of research required to produce a more thorough understanding of the relationships between local‐scale thermodynamic effects, large‐scale atmospheric circulation, and subdaily extreme rainfall intensity.
Key Points
Significant increases in rainfall intensity are expected at subdaily time scalesDescribes link between subdaily extreme rainfall and atmospheric temperatureDiscusses role of observations and modeling to help understand future change
Adhesion of erythrocytes to endothelial cells lining the vascular wall can cause vaso-occlusive events that impair blood flow which in turn may result in ischemia and tissue damage. Adhesion of ...erythrocytes to vascular endothelial cells has been described in multiple hemolytic disorders, especially in sickle cell disease, but the adhesion of normal erythrocytes to endothelial cells has hardly been described. It was shown that calcium-loaded erythrocytes can adhere to endothelial cells. Because sickle erythrocyte adhesion to ECs can be enhanced by ultra-large von Willebrand factor multimers, we investigated whether calcium loading of erythrocytes could promote binding to endothelial cells via ultra-large von Willebrand factor multimers. We used (immunofluorescent) live-cell imaging of washed erythrocytes perfused over primary endothelial cells at venular flow rate. Using this approach, we show that calcium-loaded erythrocytes strongly adhere to histamine-stimulated primary human endothelial cells. This adhesion is mediated by ultra-large von Willebrand factor multimers. Von Willebrand factor knockdown or ADAMTS13 cleavage abolished the binding of erythrocytes to activated endothelial cells under flow. Platelet depletion did not interfere with erythrocyte binding to von Willebrand factor. Our results reveal platelet-independent adhesion of calcium-loaded erythrocytes to endothelium-derived von Willebrand factor. Erythrocyte adhesion to von Willebrand factor may be particularly relevant for venous thrombosis, which is characterized by the formation of erythrocyte-rich thrombi.
Abstract
The joint detection of gravitational waves (GWs) and electromagnetic radiation from the binary neutron star (BNS) merger GW170817 has provided unprecedented insight into a wide range of ...physical processes: heavy element synthesis via the
r
-process; the production of relativistic ejecta; the equation of state of neutron stars and the nature of the merger remnant; the binary coalescence timescale; and a measurement of the Hubble constant via the “standard siren” technique. In detail, all of these results depend on the distance to the host galaxy of the merger event, NGC 4993. In this Letter we measure the surface brightness fluctuation (SBF) distance to NGC 4993 in the F110W and F160W passbands of the Wide Field Camera 3 Infrared Channel (WFC3/IR) on the
Hubble Space Telescope
(
HST
). For the preferred F110W passband we derive a distance modulus of
(
m
−
M
)
=
33.05
±
0.08
±
0.10
mag, or a linear distance
d
= 40.7 ± 1.4 ± 1.9 Mpc (random and systematic errors, respectively); a virtually identical result is obtained from the F160W data. This is the most precise distance to NGC 4993 available to date. Combining our distance measurement with the corrected recession velocity of NGC 4993 implies a Hubble constant
H
0
= 71.9 ± 7.1 km s
−1
Mpc
−1
. A comparison of our result to the GW-inferred value of
H
0
indicates a binary orbital inclination of
i
≳ 137°. The SBF technique can be applied to early-type host galaxies of BNS mergers to ∼100 Mpc with
HST
and possibly as far as ∼300 Mpc with the
James Webb Space Telescope
, thereby helping to break the inherent distance-inclination degeneracy of the GW data at distances where many future BNS mergers are likely to be detected.
The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft ...survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 n = 3,499 and 2008-2018 n = 3,781), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.
Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer's disease, but the fundamental molecular pathways that control ...their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.
We present the first results from the KMOS (K-band Multi-Object Spectrograph) AGN (active galactic nuclei) Survey at High redshift (KASHz), a VLT/KMOS integral-field spectroscopic (IFS) survey of z ≳ ...0.6 AGN. We present galaxy-integrated spectra of 89 X-ray AGN (L
2–10 keV = 1042–1045 erg s−1), for which we observed O iii (z ≈ 1.1–1.7) or Hα emission (z ≈ 0.6–1.1). The targets have X-ray luminosities representative of the parent AGN population and we explore the emission-line luminosities as a function of X-ray luminosity. For the O iii targets, ≈50 per cent have ionized gas velocities indicative of gas that is dominated by outflows and/or highly turbulent material (i.e. overall line widths ≳600 km s−1). The most luminous half (i.e. L
X > 6 × 1043 erg s−1) have a ≳2 times higher incidence of such velocities. On the basis of our results, we find no evidence that X-ray obscured AGN are more likely to host extreme kinematics than unobscured AGN. Our KASHz sample has a distribution of gas velocities that is consistent with a luminosity-matched sample of z < 0.4 AGN. This implies little evolution in the prevalence of ionized outflows, for a fixed AGN luminosity, despite an order-of-magnitude decrease in average star formation rates over this redshift range. Furthermore, we compare our Hα targets to a redshift-matched sample of star-forming galaxies and despite a similar distribution of Hα luminosities and likely star formation rates, we find extreme ionized gas velocities are up to ≈10 times more prevalent in the AGN-host galaxies. Our results reveal a high prevalence of extreme ionized gas velocities in high-luminosity X-ray AGN and imply that the most powerful ionized outflows in high-redshift galaxies are driven by AGN activity.
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