Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: ...decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies.
In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×10
per cubic millimeter and an increase from baseline of ≥20×10
per cubic millimeter without the use of rescue medication).
Sixty patients were enrolled. At baseline, the median platelet count was 15×10
per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×10
per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×10
per cubic millimeter was 65%.
Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).
We present the public release of the stellar mass catalogs for the GOODS-S and UDS fields obtained using some of the deepest near-IR images available, achieved as part of the Cosmic Assembly ...Near-infrared Deep Extragalactic Legacy Survey project. We combine the effort from 10 different teams, who computed the stellar masses using the same photometry and the same redshifts. Each team adopted their preferred fitting code, assumptions, priors, and parameter grid. The combination of results using the same underlying stellar isochrones reduces the systematics associated with the fitting code and other choices. Thanks to the availability of different estimates, we can test the effect of some specific parameters and assumptions on the stellar mass estimate. The choice of the stellar isochrone library turns out to have the largest effect on the galaxy stellar mass estimates, resulting in the largest distributions around the median value (with a semi interquartile range larger than 0.1 dex). On the other hand, for most galaxies, the stellar mass estimates are relatively insensitive to the different parameterizations of the star formation history. The inclusion of nebular emission in the model spectra does not have a significant impact for the majority of galaxies (less than a factor of 2 for ~80% of the sample). Nevertheless, the stellar mass for the subsample of young galaxies (age <100 Myr), especially in particular redshift ranges (e.g., 2.2 < z < 2.4, 3.2 < z < 3.6, and 5.5 < z < 6.5), can be seriously overestimated (by up to a factor of 10 for <20 Myr sources) if nebular contribution is ignored.
Background
Multiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence ...clinical progression.
Objective
To study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.
Methods
Healthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM
z
-scores and changes in connected GM
z
-scores, and between baseline GM
z
-scores and changes in connected WM
z
-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.
Results
We included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM
z
-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.
Discussion
Lower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.
We present here a new study of the aging of Triple-GEM detectors in contaminated environment. The goal of this experiment is to evaluate the influence of the ionization power of particles on the ...longevity of the gaseous detectors and therefore determine the best configurations required to reliably reproduce the classical aging phenomena in laboratory. A 100 cm2 triple-GEM detector operating in Ar/CO2 (70/30%) was irradiated simultaneously with low energy X-rays and 5.5 MeV alpha particles. Hydrocarbons and Si-based molecules were added to the gas mixture in order to accelerate the aging and simulating many years of slow gas pollution. We measured the evolution of the detector performance in two irradiated zones and we performed a systematic chemical analysis of the GEM foils to measure the polymer concentration and thus the potential aging effects. The detector collected a total charge of 165 mC/cm2 in the two irradiated sectors with no performance loss. Chemical analysis revealed a greater Si-based polymers concentration in the region irradiated with alpha particles. This is due to their higher ionization power, with respect to low energy X-rays, which generate denser electron avalanches and, thus, a higher polymerization rate. Further studies have to be performed in order to validate this result, at different experimental conditions and with different detector technologies.
Ayahuasca is a natural psychoactive brew, used in traditional ceremonies in the Amazon basin. Recent research has indicated that ayahuasca is pharmacologically safe and its use may be positively ...associated with improvements in psychiatric symptoms. The mechanistic effects of ayahuasca are yet to be fully established. In this prospective naturalistic study, 63 self-selected participants took part in ayahuasca ceremonies at a retreat centre in the Peruvian Amazon. Participants undertook the Beck Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI), Self-compassion Scale (SCS), Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM), as well as secondary measures, pre- and post-retreat and at 6-months. Participants also provided saliva samples for pre/post epigenetic analysis. Overall, a statistically significant decrease in BDI-II (13.9 vs. 6.1,
p
< 0.001), STAI (44.4 vs. 34.3
p
< 0.001) scores, and CORE-OM scores were observed (37.3 vs. 22.3
p
< 0.001) at post-retreat, as well as a concurrent increase in SCS (3.1 vs. 3.6,
p
< 0.001). Psychometric improvements were sustained, and on some measures values further decreased at 6-month follow-up, suggesting a potential for lasting therapeutic effects. Changes in memory valence were linked to the observed psychometric improvements. Epigenetic findings were equivocal, but indicated that further research in candidate genes, such as sigma non-opioid intracellular receptor 1 (SIGMAR1), is warranted. This data adds to the literature supporting ayahuasca's possible positive impact on mental health when conducted in a ceremonial context. Further investigation into clinical samples, as well as greater analyses into the mechanistic action of ayahuasca is advised.
Trends in utilization of Emergency Medical Services (EMS) systems can be used to extrapolate future use of an EMS system, which will be valuable for the budgeting and planning of finances and ...resources. The best model for incorporation of seasonal and regional fluctuations in utilization to predict future utilization is unknown.
Authors aimed to trend patterns of utilization in a regional EMS system to identify the needs of a growing population and to allow for a better understanding of how the EMS system is used on a basis of call volume and frequency of EMS transportation. The authors then used a best-fitting prediction model approach to show how the studied EMS system will be used in future years.
Systems data were retrospectively extracted by using the electronic medical records of the studied EMS system and its computer-assisted dispatch (CAD) database from 2010 through 2017. All EMS dispatches entering the system's 9-1-1 public service access point were captured. Annual utilization data were available from 2010 through 2017, while quarterly data were available only from 2013 through 2017. The 9-1-1 utilization per capita, Advanced Life Support (ALS) utilization per capita, and ALS cancel rates were calculated and trended over the study period. The methods of prediction were assessed through a best-fitting model approach, which statistically suggested that Additive Winter's approach (SAS) was the best fit to determine future utilization and ALS cancel rates.
Total 9-1-1 call volume per capita increased by 32.46% between 2010 and 2017, with an average quarterly increase of 0.78% between 2013 and 2017. Total ALS call volume per capita increased by 1.93% between 2010 and 2017. Percent ALS cancellations (cancelled en route to scene) increased by eight percent between 2010 and 2017, with an average quarterly increase of 0.42% (2013-2017). Predictions to end of 2019 using Additive Winter's approach demonstrated increasing trends in 9-1-1 call volume per capita (R2 = 0.47), increasing trends of ALS utilization per capita (R2 = 0.71), and increasing percent ALS cancellation (R2 = 0.93). Each prediction showed increasing future trends with a 95% confidence interval.
The authors demonstrate paramount per capita increases of 9-1-1 call volume in the studied ALS system. There are concomitant increases of ALS cancellations prior to arrival, which suggests a potential burden on this regional ALS response system.
In 2017, Tamil Nadu, a southern state, had the second highest number of dengue cases from India. In the present study, the serotype‐specific differences in the clinical manifestations and laboratory ...parameters among hospitalized children with dengue were investigated and molecular characterization of the circulating dengue virus (DENV) serotypes during 2017 in Tamil Nadu was performed. Eighty children with dengue‐like symptoms consecutively admitted to a tertiary care hospital and positive for DENV NS1 antigen were investigated for DENV serotype utilizing a real‐time reverse transcriptase based polymerase chain reaction assay. Complete envelope (E) gene sequencing of the DENV strains was performed. Seventy samples were positive for serotyping (25 DENV‐1, 17 DENV‐2, six DENV‐3, and 22 DENV‐4). DENV‐4 infections were associated with elevated levels of liver enzymes; Alanine aminotransferase (P = .021) and aspartate aminotransferase (P = .001). However, none of the serotype was associated with any specific clinical features and severe dengue. Asian and American/African genotypes of DENV‐1 were cocirculating. The circulating genotype was cosmopolitan for DENV‐2 with multiple lineages, genotype III for DENV‐3 and genotype I for DENV‐4. Unique mutations were present in the 2017 DENV‐4 isolates. The present study suggests the association of DENV‐4 with elevated liver enzymes in children hospitalized for dengue. Further, the study reports the genetic diversity of DENV circulating in Tamil Nadu during 2017. The study calls for continuous monitoring of the circulating serotypes and genotypes at regional level in India which might result in a region wise database useful in predicting future outbreaks.
Research Highlights
In Tamil Nadu, India, Asian and American/African genotypes of DENV‐1, cosmopolitan genotype of DENV‐2, genotype III of DENV‐3 and genotype I of DENV‐4 strains were circulating during 2017.
DENV‐4 was associated with elevated levels of liver enzymes in children hospitalized for dengue.
DENV serotypes were not associated with disease severity in children hospitalized for dengue.
The study calls for continuous monitoring of the circulating serotypes and genotypes at regional level in India.
The measurement of the luminosity recorded by the CMS detector installed at LHC interaction point 5, using proton–proton collisions at
s
=
13
TeV
in 2015 and 2016, is reported. The absolute ...luminosity scale is measured for individual bunch crossings using beam-separation scans (the van der Meer method), with a relative precision of 1.3 and 1.0% in 2015 and 2016, respectively. The dominant sources of uncertainty are related to residual differences between the measured beam positions and the ones provided by the operational settings of the LHC magnets, the factorizability of the proton bunch spatial density functions in the coordinates transverse to the beam direction, and the modeling of the effect of electromagnetic interactions among protons in the colliding bunches. When applying the van der Meer calibration to the entire run periods, the integrated luminosities when CMS was fully operational are 2.27 and 36.3
fb
-
1
in 2015 and 2016, with a relative precision of 1.6 and 1.2%, respectively. These are among the most precise luminosity measurements at bunched-beam hadron colliders.
Aim: Neutrophil migration in the intestine depends on chemotaxis of neutrophils to CXC chemokines produced by epithelial cells. The goal of this project was to determine if acute induction of a CXC ...chemokine gradient originating from intestinal epithelial cells is sufficient to induce neutrophil influx into intact intestinal tissue. Methods and results: The authors developed a double transgenic mouse model with doxycycline induced human IL-8 expression restricted to intestinal epithelial cells. Doxycycline treatment of double transgenic mice for three days resulted in a 50-fold increase in the caecal IL-8 concentration and influx of neutrophils into the lamina propria. Although neutrophils entered the paracellular space between epithelial cells, complete transepithelial migration was not observed. Doxycycline treatment also increased the water content of the caecal and colonic stool, indicating dysfunctional water transport. However, the transmural electrical resistance was not decreased. Neutrophils recruited to the intestinal epithelium did not show evidence of degranulation and the epithelium remained intact as judged by histology. Conclusions: This conditional transgenic model of chemokine expression provides evidence that acute induction of IL-8 in the intestinal epithelium is sufficient to trigger neutrophil recruitment to the lamina propria, but additional activation signals are needed for full activation and degranulation of neutrophils, mucosal injury, and complete transepithelial migration.
PDF
