Current guidelines favor 4F-PCC over plasma for warfarin reversal. Uncertainty remains on its thrombotic risk and hemostatic effectiveness when used for direct-acting oral anticoagulants (DOACs), ...transplants, massive transfusion protocols (MTP), and non-anticoagulated patients. This study sought to evaluate the tolerability and effectiveness of 4F-PCC in a real-world setting.
This was a retrospective study of adults who received 4F-PCC from March 2014 to December 2015. The primary outcome was thromboembolic events within 14 days. The secondary outcome was hemostatic effectiveness within 24 h.
The final analysis included 212 patients. Primary reversal indication was major bleed in 165 patients (77.8%) and emergent surgery in 47 patients (22.2%). Thromboembolism occurred in 22 patients (10.4%), more in emergent surgery than major bleed reversals (17% and 8.5%, respectively). MTP and heart transplant patients had the highest thromboembolic event rates (44.4% and 28.6%, respectively). Hemostatic effectiveness was 65.8% (68% in major bleed and 58.1% in emergent surgery). DOAC patients achieved hemostasis most often (78.9%). Administration of any reversal agent, major surgery within 14 days, and MTP activation were significant predictors of thromboembolism.
Use of 4F-PCC in this real-world setting was associated with variable thromboembolic and hemostatic effectiveness rates based on the indication for reversal.
•4F-PCC is standard care for warfarin reversal in major bleed and emergent surgery.•4F-PCC is also used in non-warfarin reversals despite limited evidence.•Significant thrombotic predictors were use of any reversal agent and major surgery.•Lower hemostatic effectiveness and higher thromboses than in prospective trials.•These data offer added risk/benefit evidence for 4F-PCC in non-warfarin reversals.
We present simulations of the magnetized interstellar medium (ISM) in models of massive star-forming (40 M sub(middot in circle) yr super(-1)) disk galaxies with high gas surface densities ( capital ...sigma sub(gas) ~ 100 M sub(middot in circle) pc super(-2)) similar to observed star-forming high-redshift disks. We assume that type II supernovae deposit 10% of their energy into the ISM as cosmic rays (CRs) and neglect the additional deposition of thermal energy or momentum. With a typical Galactic diffusion coefficient for CRs (3 x 10 super(28) cm super(2) s super(-1)), we demonstrate that this process alone can trigger the local formation of a strong low-density galactic wind maintaining vertically open field lines. Driven by the additional pressure gradient of the relativistic fluid, the wind speed can exceed 10 super(3) km s super(-1), much higher than the escape velocity of the galaxy. The global mass loading, i.e., the ratio of the gas mass leaving the galactic disk in a wind to the star formation rate, becomes of order unity once the system has settled into an equilibrium. We conclude that relativistic particles accelerated in supernova remnants alone provide a natural and efficient mechanism to trigger winds similar to observed mass-loaded galactic winds in high-redshift galaxies. These winds also help in explaining the low efficiencies for the conversion of gas into stars in galaxies, as well as the early enrichment of the intergalactic medium with metals. This mechanism may be at least of similar importance to the traditionally considered momentum feedback from massive stars and thermal and kinetic feedback from supernova explosions.
Autonomic symptoms in alcohol withdrawal syndrome (AWS) are associated with a sympathetic-driven imbalance of the autonomic nervous system. To restore autonomic balance in AWS, novel neuromodulatory ...approaches could be beneficial. We conducted a pilot trial with percutaneous auricular vagus nerve stimulation (pVNS) in AWS and hypothesized that pVNS will enhance the parasympathetic tone represented by a reduction of pupillary dilation in a parasympatholytic pharmacological challenge.
Thirty patients suffering from alcohol use disorder, undergoing AWS, and stable on medication, were recruited in this open-label, single-arm pilot trial with repeated-measure design. Peripheral VNS (monophasic volt impulses of 1 msec, alternating polarity, frequency 1 Hz, amplitude 4 mV) was administered at the left cymba conchae for 72 h, followed by pupillometry under a tropicamide challenge. We assessed craving with a visual analog scale. We used pupillary mean as the dependent variable in a repeated-measures ANOVA (rmANOVA).
A repeated-measures ANOVA resulted in a significant difference for pupillary diameter across time and condition (F(2,116) = 27.97, p < .001, ηp2 > .14). Tukey-adjusted post hoc analysis revealed a significant reduction of pupillary diameter after pVNS. Alcohol craving was significantly reduced after pVNS (p < .05, Cohen's d = 1.27).
Our study suggests that pVNS activates the parasympathetic nervous system in patients with acute AWS, and that this activation is measurable by pupillometry. To this end, pVNS could be beneficial as a supportive therapy for AWS. Potential confounding effects of anti-craving treatment should be kept in mind.
•pVNS inhibits pupil dilation in an anticholinergic challenge in alcohol withdrawal syndrome.•Novel neuromodulatory techniques may have the potential to mitigate symptoms of alcohol withdrawal syndrome.•pVNS decreased alcohol craving, though this effect could be confounded by treatment.
Abstract Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) ...inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. Hypoalgesia was observed in NET KO mice, and to a lesser extent in SERT KO mice. The magnitude of this hypoalgesia in NET KO mice was so profound that it limited the assessment of drug-induced analgesia. Nonetheless, the necessary exclusion of these subjects because of profound baseline hypoalgesia strongly supports the role of norepinephrine and NET in basal nociceptive behavior while indicating a much smaller role for serotonin and SERT. To further clarify the role of NET and SERT in basal nociceptive sensitivity further experiments were conducted in SERT KO and NET KO mice across a range of temperatures. NET KO mice were again found to have pronounced thermal hypoalgesia compared to WT mice in both the hotplate and tail-flick tests, while only limited effects were observed in SERT KO mice. Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no change in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice.
In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families ...linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
Background
There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of ...particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no “spontaneous improvement” prior to treatment initiation (high‐severity population) than in a mild‐severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD.
Methods
We conducted a systematic literature review on placebo‐controlled RCTs for AD.We assigned retained RCTs to high‐ or mild‐severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta‐regression analysis.
Results
Among the 19 retained RCTs (comprising 1996 placebo‐treated patients), 11 trials were high‐severity and 8 were mild‐severity RCTs. The between‐study variability in AR was lower in the high‐severity than in the mild‐severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high‐severity studies (16.8% at 3 months) than the mild‐severity studies (36.7% at 3 months).
Conclusions
Pharmacological RCTs for AD should select high‐severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.
Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity ...disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.
Effective management of the soil resource requires basic information about the spatial distribution of various attributes. A method widely used for providing spatial information is a combination of ...sampling strategies and geostatistics. However, geostatistical methods demand intensive sampling that is expensive and time-consuming. Geophysical methods, such as electromagnetic (EM) induction, offer an alternative, more robust, and less expensive approach to gather soil information. In this study, a methodology is outlined for mapping spatial distribution of bulk soil average clay content to a depth of 7
m using EM measurements. The study was conducted southeast of Trangie in the lower Macquarie valley of New South Wales, Australia. Two EM sensors were employed. To provide deep bulk soil EM measurements, an EM34 was used in the horizontal dipole mode at coil configurations of 10, 20, and 40
m (respectively, designated EM34-10, EM34-20, and EM34-40). For shallower bulk soil EM measurements, an EM38 was used in vertical and horizontal modes (EM38-v and EM38-h, respectively). A total of 755 locations were measured on a grid of approximately 0.5
km. In order to classify the EM34 data into broad physiographic and hydrogeological units, fuzzy
k-means (FKM) classification was applied. By iterating fuzziness exponents (
ϕ), input parameters, and evaluating various clustering performance indices, we found optimal classification when
ϕ
=
1.5 and number of classes (
c)
=
4. Fuzzy
k-means with extragrade (FKMe) classification was subsequently undertaken to account for Extragrades (i.e., outliers in the data). A spatial response surface sampling (SRSS) design was invoked to select sampling sites within each of the four regular and one Extragrade class. From 40 calibration holes (i.e., 8 from each class), soil samples were taken at 1
m intervals from the soil surface to a depth of 7
m. Each sample was analyzed for clay content then averaged for a 0–7
m clay content (%clay) for each hole. In order to predict the %clay across the landscape, a hierarchical spatial regression model (HSR) was developed using a composite signal variable i.e., ln(EM34-10)
+
ln(EM34-40)
+
ln(EM38-h) and first-order trend surface components (i.e., Easting and Northing). The final map of %clay generally reflects the known surface clay content and provides information about the spatial distribution of subsurface %clay variability. We conclude that although the FKMe analysis did not result in an improved calibration within each class, the approach delineated similar clusters of signal readings that were useful in providing a framework to determine a soil sampling design that accounted for variations in physiography and hydrogeology.
Scarce freshwater resources in arid and semiarid regions means that recreational landscapes should use recycled or low-quality waters for irrigation, increasing the risk of salinity and infiltration ...problems. We map salinity distribution within turf fields using electromagnetic sensing, evaluate need for leaching and evaluate post leaching results for subsequent management decisions. Electromagnetic measurements were made with two EM38 instruments positioned vertically and horizontally in order to determine salinity distribution. Sensor readings were coupled to GPS data to create spatial salinity maps. Next, optimal calibration point coordinates were determined via Electrical Conductivity Sampling Assessment and Prediction (ESAP) software. Soil samples from 0-15 and 15-30 cm depths were used for each calibration point. Laboratory soil saturation percentage, moisture content, electrical conductivity (EC
) and pH
of saturation extracts were determined for calibration to convert resistivity measurements to EC
. Next, EC
maps were created using ESAP software. Leaching for reclamation was performed by means of sprinkling. Treated municipal wastewater was utilized both for irrigation and for reclamation leaching. Low water content and high spatial variability of soil texture adversely affected the accuracy of the readings. Pre and post leaching surveys indicate that in one fairway there was only a 43% and 58% decrease in soil salinity at 0-15 and 15-30 cm depths, respectively which is very low relative to expected results considering the amount of water applied. This relatively low reduction in salinity and the lack of runoff during irrigation combined with infiltration measurements suggests that aeration techniques for healthier grasses led to water bypassing small pores thus limiting leaching efficiency. In this instance practices to improve infiltration lead paradoxically to less salinity reclamation than expected.
Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only ...modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol‐dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol‐dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol‐mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new—as yet unpublished—large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO‐defined DRLs and (d) from multiple meta‐analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol‐dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ‐hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol‐dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well‐tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol‐dependent patients with VH DRL.
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