Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABA
R) internalization that ...follows prolonged SE; this receptor trafficking results in fewer GABA
R in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.
Abstract
This reviews the transition of remote monitoring of patients with cardiac electronic implantable devices from curiosity to standard of care. This has been delivered by technology evolution ...from patient-activated remote interrogations at appointed intervals to continuous monitoring that automatically flags clinically actionable information to the clinic for review. This model has facilitated follow-up and received professional society recommendations. Additionally, continuous monitoring has provided a new level of granularity of diagnostic data enabling extension of patient management from device to disease management. This ushers in an era of digital medicine with wider applications in cardiovascular medicine.
Traumatic hemorrhage represents a major cause of mortality in low-income and middle-income countries (LMICs). Thus, LMICs can benefit from improvements to prehospital hemorrhage management. One ...strategy is implementation of a bleeding control course using the “train the trainer” model (TTT) to increase course availability. The Stop the Bleed (STB) campaign provides laypeople with basic knowledge and skills of hemorrhage control. While the feasibility and success of the STB course have been demonstrated in the United States, course dissemination in LMICs has been slower and its feasibility using the TTT model has not been established.
From December 2017 to January 2019, instructors from the International Surgical Health Initiative conducted seven surgical humanitarian trips and taught 10 index 1-h STB training sessions across six LMICs. LMIC instructors were encouraged to continue providing STB courses following departure of the visiting instructors. Course data were collected from sign-in sheets and analyzed using Microsoft Excel.
Ten index courses conducted by United States–trained STB experts trained 35 LMIC instructors over 2 y. Six of 35 offered 12 additional courses, certifying 323 new trainees, an 823% increase from the initial cohort. Overall, implementation of the TTT model yielded 22 STB courses in six LMICs, producing 358 new trainees.
This pilot study shows the STB TTT model was feasible and effective in expanding bleeding control trainer capacity in four of six LMICs. Use of the TTT model in LMICs may represent a means to increase STB course availability and is one strategy to improve prehospital hemorrhage control in LMICs.
•The train-the-trainer (TTT) model can effectively expand bleeding control in low-income and middle-income countries (LMICs).•The TTT model can empower LMIC trainers to sustain Stop the Bleed courses locally.•Further use of the TTT model may improve prehospital hemorrhage control in LMICs.
Since digital devices are increasingly used in cardiology for assessing cardiac rhythm and detecting arrhythmias, especially atrial fibrillation (AF), our aim was to evaluate the expectations and ...opinions of healthcare professionals in Europe on reimbursement policies for the use of digital devices (including wearables) in AF and other arrhythmias. An anonymous survey was proposed through announcements on the European Heart Rhythm Association website, social media channels, and mail newsletter. Two hundred and seventeen healthcare professionals participated in the survey: 32.7%, reported regular use of digital devices, 45.2% reported that they sometimes use these tools, 18.6% that they do not use but would like to. Only a minority (3.5%) reported a lack of trust in digital devices. The survey highlighted a general propensity to provide medical consultation for suspected AF or other arrhythmias detected by a consumer-initiated use of digital devices, even if time constraints and reimbursement availability emerged as important elements. More than 85% of respondents agreed that reimbursement should be applied for clinical use of digital devices, also in different settings such as post-stroke, post-cardioversion, post-ablation, and in patients with palpitations or syncope. Finally, 73.6% of respondents confirmed a lack of reimbursement fees in their country for physicians' consultations (tracings interpretation) related to digital devices. Digital devices, including wearables, are increasingly and widely used for assessing cardiac rhythm and detecting AF, but a definition of reimbursement policies for physicians' consultations is needed.
Context. The APEX Telescope Large Area Survey of the GALaxy (ATLASGAL) is the first systematic survey of the inner Galactic plane in the sub-millimetre. The observations were carried out with the ...Large APEX Bolometer Camera (LABOCA), an array of 295 bolometers observing at 870 μm (345 GHz). Aims. Here we present a first version of the compact source catalogue extracted from this survey. This catalogue provides an unbiased database of dusty clumps in the inner Galaxy. Methods. The construction of this catalogue was made using the source extraction routine SExtractor. We have cross-associated the obtained sources with the IRAS and MSX catalogues, in order to constrain their nature. Results. We have detected 6639 compact sources in the range from 330 ≤ ℓ ≤ 21 degrees and |b| ≤ 1.5 degrees. The catalogue has a 99% completeness for sources with a peak flux above 6σ, which corresponds to a flux density of ~0.4 Jy beam-1. The parameters extracted for sources with peak fluxes below the 6σ completeness threshold should be used with caution. Tests on simulated data find the uncertainty in the flux measurement to be ~12%, however, in more complex regions the flux values can be overestimated by a factor of 2 due to the additional background emission. Using a search radius of 30′′ we found that 40% of ATLASGAL compact sources are associated with an IRAS or MSX point source, but, ~50% are found to be associated with MSX 21 μm fluxes above the local background level, which is probably a lower limit to the actual number of sources associated with star formation. Conclusions. Although infrared emission is found towards the majority of the clumps detected, this catalogue is still likely to include a significant number of clumps that are devoid of star formation activity and therefore excellent candidates for objects in the coldest, earliest stages of (high-mass) star formation.
Context.
Molecular clouds, which harbor the birthplaces of stars, form out of the atomic phase of the interstellar medium (ISM). To understand this transition process, it is crucial to investigate ...the spatial and kinematic relationships between atomic and molecular gas.
Aims.
We aim to characterize the atomic and molecular phases of the ISM and set their physical properties into the context of cloud formation processes.
Methods.
We studied the cold neutral medium (CNM) by means of H
I
self-absorption (HISA) toward the giant molecular filament GMF20.0-17.9 (distance = 3.5 kpc, length ~170 pc) and compared our results with molecular gas traced by
13
CO emission. We fitted baselines of HISA features to H
I
emission spectra using first and second order polynomial functions.
Results.
The CNM identified by this method spatially correlates with the morphology of the molecular gas toward the western region. However, no spatial correlation between HISA and
13
CO is evident toward the eastern part of the filament. The distribution of HISA peak velocities and line widths agrees well with
13
CO within the whole filament. The column densities of the CNM probed by HISA are on the order of 10
20
cm
−2
while those of molecular hydrogen traced by
13
CO are an order of magnitude higher. The column density probability density functions (N-PDFs) of HISA (CNM) and H
I
emission (tracing both the CNM and the warm neutral medium, WNM) have a log-normal shape for all parts of the filament, indicative of turbulent motions as the main driver for these structures. The H
2
N-PDFs show a broad log-normal distribution with a power-law tail suggesting the onset of gravitational contraction. The saturation of H
I
column density is observed at ~25
M
⊙
pc
−2
.
Conclusions.
We conjecture that different evolutionary stages are evident within the filament. In the eastern region, we witness the onset of molecular cloud formation out of the atomic gas reservoir while the western part is more evolved, as it reveals pronounced H
2
column density peaks and signs of active star formation.
Sequence diversity and gene content distinguish most isolates of Helicobacter pylori. Even greater sequence differences differentiate distinct populations of H. pylori from different continents, but ...it was not clear whether these populations also differ in gene content. To address this question, we tested 56 globally representative strains of H. pylori and four strains of Helicobacter acinonychis with whole genome microarrays. Of the weighted average of 1,531 genes present in the two sequenced genomes, 25% are absent in at least one strain of H. pylori and 21% were absent or variable in H. acinonychis. We extrapolate that the core genome present in all isolates of H. pylori contains 1,111 genes. Variable genes tend to be small and possess unusual GC content; many of them have probably been imported by horizontal gene transfer. Phylogenetic trees based on the microarray data differ from those based on sequences of seven genes from the core genome. These discrepancies are due to homoplasies resulting from independent gene loss by deletion or recombination in multiple strains, which distort phylogenetic patterns. The patterns of these discrepancies versus population structure allow a reconstruction of the timing of the acquisition of variable genes within this species. Variable genes that are located within the cag pathogenicity island were apparently first acquired en bloc after speciation. In contrast, most other variable genes are of unknown function or encode restriction/modification enzymes, transposases, or outer membrane proteins. These seem to have been acquired prior to speciation of H. pylori and were subsequently lost by convergent evolution within individual strains. Thus, the use of microarrays can reveal patterns of gene gain or loss when examined within a phylogenetic context that is based on sequences of core genes.
Context.
The atomic phase of the interstellar medium plays a key role in the formation process of molecular clouds. Due to the line-of-sight confusion in the Galactic plane that is associated with ...its ubiquity, atomic hydrogen emission has been challenging to study.
Aims.
We investigate the physical properties of the “Maggie” filament, a large-scale filament identified in H
I
emission at line-of-sight velocities,
v
LSR
~−54 km s
−1
.
Methods.
Employing the high-angular resolution data from The H
I
/OH Recombination line survey of the inner Milky Way (THOR), we have been able to study H
I
emission features at negative
v
LSR
velocities without any line-of-sight confusion due to the kinematic distance ambiguity in the first Galactic quadrant. In order to investigate the kinematic structure, we decomposed the emission spectra using the automated Gaussian fitting algorithm G
AUSS
P
Y
+.
Results.
We identify one of the largest, coherent, mostly atomic H
I
filaments in the Milky Way. The giant atomic filament Maggie, with a total length of 1.2 ± 0.1 kpc, is not detected in most other tracers, and it does not show signs of active star formation. At a kinematic distance of 17 kpc, Maggie is situated below (by ≈500 pc), but parallel to, the Galactic H
I
disk and is trailing the predicted location of the Outer Arm by 5−10 km s
−1
in longitude-velocity space. The centroid velocity exhibits a smooth gradient of less than ±3 km s
−1
(10 pc)
−1
and a coherent structure to within ±6 km s
−1
. The line widths of ~10 km s
−1
along the spine of the filament are dominated by nonthermal effects. After correcting for optical depth effects, the mass of Maggie’s dense spine is estimated to be 7.2
−1.9
+2.5
× 10
5
M
⊙
. The mean number density of the filament is ~4 cm
−3
, which is best explained by the filament being a mix of cold and warm neutral gas. In contrast to molecular filaments, the turbulent Mach number and velocity structure function suggest that Maggie is driven by transonic to moderately supersonic velocities that are likely associated with the Galactic potential rather than being subject to the effects of self-gravity or stellar feedback. The probability density function of the column density displays a log-normal shape around a mean of ⟨
N
H
I
⟩ = 4.8 × 10
20
cm
−2
, thus reflecting the absence of dominating effects of gravitational contraction.
Conclusions.
While Maggie’s origin remains unclear, we hypothesize that Maggie could be the first in a class of atomic clouds that are the precursors of giant molecular filaments.
We present ~kiloparsec spatial resolution maps of the CO-to-H2 conversion factor (αCO) and dust-to-gas ratio (DGR) in 26 nearby, star-forming galaxies. We have simultaneously solved for αCO and the ...DGR by assuming that the DGR is approximately constant on kiloparsec scales. With this assumption, we can combine maps of dust mass surface density, CO-integrated intensity, and H I column density to solve for both αCO and the DGR with no assumptions about their value or dependence on metallicity or other parameters. Such a study has just become possible with the availability of high-resolution far-IR maps from the Herschel key program KINGFISH, 12CO J = (2-1) maps from the IRAM 30 m large program HERACLES, and H I 21 cm line maps from THINGS. We use a fixed ratio between the (2-1) and (1-0) lines to present our αCO results on the more typically used 12CO J = (1-0) scale and show using literature measurements that variations in the line ratio do not affect our results. In total, we derive 782 individual solutions for αCO and the DGR. On average, αCO = 3.1 M ⊙ pc-2 (K km s-1)-1 for our sample with a standard deviation of 0.3 dex. Within galaxies, we observe a generally flat profile of αCO as a function of galactocentric radius. However, most galaxies exhibit a lower αCO value in the central kiloparsec—a factor of ~2 below the galaxy mean, on average. In some cases, the central αCO value can be factors of 5-10 below the standard Milky Way (MW) value of αCO, MW = 4.4 M ⊙ pc-2 (K km s-1)-1. While for αCO we find only weak correlations with metallicity, the DGR is well-correlated with metallicity, with an approximately linear slope. Finally, we present several recommendations for choosing an appropriate αCO for studies of nearby galaxies.
Context. OH masers trace diverse physical processes, from the expanding envelopes around evolved stars to star-forming regions or supernovae remnants. Providing a survey of the ground-state OH maser ...transitions in the northern hemisphere inner Milky Way facilitates the study of a broad range of scientific topics. Aims. We want to identify the ground-state OH masers at ∼18 cm wavelength in the area covered by The HI/OH/Recombination line survey of the Milky Way (THOR). We will present a catalogue of all OH maser features and their possible associated environments. Methods. The THOR survey covers longitude and latitude ranges of 14.°3 < l < 66.°8 14 . ° 3 < l < 66 . ° 8 $ 14{{\overset{\circ}{.}}}3 < l < 66{{\overset{\circ}{.}}}8 $ and b < ± 1.°25 b < ± 1 . ° 25 $ b < \,{\pm}\,1{{\overset{\circ}{.}}}25 $ . All OH ground state lines 2Π3/2 (J = 3/2) at 1612 (F = 1−2), 1665 (F = 1−1), 1667 (F = 2−2) and 1720 MHz (F = 2−1) have been observed, employing the Very Large Array (VLA) in its C configuration. The spatial resolution of the data varies between 12.5″ and 19″, the spectral resolution is 1.5 km s−1, and the rms sensitivity of the data is ∼10 mJy beam−1 per channel. Results. We identify 1585 individual maser spots (corresponding to single spectral features) distributed over 807 maser sites (regions of size ∼103 − 104 AU). Based on different criteria from spectral profiles to literature comparison, we try to associate the maser sites with astrophysical source types. Approximately 51% of the sites exhibit the double-horned 1612 MHz spectra typically emitted from the expanding shells of evolved stars. The separations of the two main velocity features of the expanding shells typically vary between 22 and 38 km s−1. In addition to this, at least 20% of the maser sites are associated with star-forming regions. While the largest fraction of 1720 MHz maser spots (21 out of 53) is associated with supernova remnants, a significant fraction of the 1720 MHz maser spots (17) are also associated with star-forming regions. We present comparisons to the thermal 13CO(1–0) emission as well as to other surveys of class II CH3OH and H2O maser emission. The catalogue attempts to present associations to astrophysical sources where available, and the full catalogue is available in electronic form. Conclusions. This OH maser catalogue presents a unique resource of stellar and interstellar masers in the northern hemisphere. It provides the basis for a diverse range of follow-up studies from envelopes around evolved stars to star-forming regions and Supernova remnants.
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